Clearance & Elimination detail explanation.pptx

DRUG ELIMINATION
Drug elimination refers to
“Irreversible removal of drug from the body by all
routes of elimination.”
The declining plasma drug concentration observed after systemic
drug absorption shows that the drug is being eliminated from the
body but does not indicate which elimination processes are involved.
Major eliminating organs: Kidney & Liver

DRUG EXCRETION
Drug excretion is
“Removal of the intact drug”
Nonvolatile drugs are excreted mainly by renal excretion, a process
in which the drug passes through the kidney to the bladder and
ultimately into the urine. Volatile drugs, such as gaseous anesthetics,
alcohol, or drugs with high volatility, are excreted via the lungs into
expired air.
Other pathways for drug excretion may include the excretion of drug
into bile, sweat, saliva, milk (via lactation), or other body fluids.

DRUG METABOLISM
Biotransformation or drug metabolism is
“the process by which the drug is chemically converted in
the body to a metabolite.”
Biotransformation is usually an enzymatic process. A few drugs may also
be changed chemically by a non-enzymatic process (eg, ester hydrolysis).
The enzymes involved in the biotransformation of drugs are located
mainly in the liver.
Other tissues such as kidney, lung, small intestine, and skin also contain
biotransformation enzymes.

CONTENTS
DRUG CLEARANCE
Introduction and mechanism
Models
Determination of Clearance
Relationship of clearance with
half life and volume of
distribution
ELIMINATION OF DRUGS
Hepatic elimination (Percent of Drug
Metabolized, Drug Biotransformation
reactions, (Phase-I reactions and phase-II
reactions), First pass effect, Hepatic clearance
of protein bound drugs and Biliary excretion
of drugs.)
Renal excretion (Renal clearance,
Tubular Secretion and Tubular
Reabsorption.)
Elimination of drugs through
other organs (Pulmonary excretion,
Salivary excretion, Mammary excretion, Skin
excretion and Genital excretion.)

DRUG ELIMINATION
Kidney
Renal drug
excretion
Renal clearance
(DRUG
CLEARANCE)
Determination of
renal clearance
Liver
Biotransformation
of drug & 1st pass
effect
Hepatic clearance
& its
determination
Biliary clearance
Other
Pulmonary
excretion
Salivary excretion,
Mammary
excretion
Skin excretion &
Genital excretion

 Drug elimination is described in terms of clearance
from a well stirred compartment containing uniform
drug distribution
 Clearance may be defined as the volume of the fluid
cleared of drug from the body per unit of time
 The term clearance describes the process of drug
elimination from the body or from a single organ
without identifying the individual processes involved.
 Units for clearance  ml/min or L/hr

WHY STUDY ELIMINATION & CLEARANCE????

RENAL DRUG EXCRETION
• Major route of elimination for many drugs
• Drugs that are NON VOLATILE, WATER SOLUBLE,
have a LOW MOLECULAR WEIGHT or are SLOWLY
BIOTRANSFORMED BY THE LIVER are eliminated by
renal excretion
• The processes by which a drug is excreted via the
kidneys may include any combination of the
following:
 Glomerular filtration
 Active tubular secretion
 Tubular reabsorption

GF and ATS tends to increase the concentration of drugs in lumen and
hence facilitate excretion whereas TR decreases it and prevents the
movement of drug out of the body.
Thus, rate of excretion can be given as:
Rate of excretion = Rate of filtration + Rate of secretion – Rate of
reabsorption

GLOMERULAR FILTRATION
• Is a unidirectional process
• It occurs for most small molecules (MW< 500) including
undissociated (unionized) and dissociated (ionized) drugs.
• Protein bound drugs behave as large molecules and do not get
filtered at the glomerulus
• The major driving force for glomerular filtration is the hydrostatic
pressure within the glomerular capillaries
• The kidneys receive a large blood supply (approx. 25% of the cardiac
output) via the renal artery, with very little decrease in the
hydrostatic pressure.

RATE(GFR)
“ it estimates that how much blood passes through the
glomeruli each minute”
• It is measured by using a drug that is eliminated by filtration only (ie,
the drug is neither reabsorbed nor secreted)
• Examples of such drugs are inulin and creatinine
• Therefore, the clearance of inulin = GFR, which is equal to 125-130
mL/min

RATE(GFR)
• Glomerular filtration of drugs is directly related to the free or
nonprotein-bound drug conc. in the plasma
• As the free drug conc. in the plasma increases , the glomerular
filtration for the drug increases proportionately, thus
increasing renal drug clearance for some drugs
• Glomerular filtration rate (GFR) is a test used to check how
well the kidneys are working.

ACTIVE TUBULAR
SECRETION
• Is an active transport process
• Active renal secretion is a carrier mediated system that
requires energy input, b/c the drug is transported against
a conc. gradient
• The carrier system is capacity limited and may be
saturated
• Drugs with similar structures may compete for the same
carrier system
• Two active renal secretion systems have been identified,
systems for
1) Weak acids (Organic anion transporter OAT)
2) Weak bases (Organic cation transporter OCT)

• Active tubular secretion rate is dependent on renal plasma flow
• Drugs commonly used to measure active tubular secretion:
 p-amino-hipuric acid (PAH) and iodopyracet (diodrast)
• For a drug that is excreted solely by glomerular filtration, the
elimination half life may change markedly in accordance with the
binding affinity of the drug for plasma proteins
• In contrast, drug protein binding has very little effect on the
elimination half life of the drug excreted mostly by active
secretion (b/c drug protein binding is reversible, drug bound to
plasma protein rapidly dissociates as free drug is secreted by the
kidneys)
Example: some of the penicillins are extensively protein bound, but
their elimination half lives are short due to rapid elimination by
active secretion.

TUBULAR REABSORPTION
• Occurs after the drug is filtered through the
glomerulus and can be an active or a passive process
• If a drug is completely reabsorbed (eg, glucose), then
the value for the clearance of the drug is
approximately zero.
• For drugs that are partially reabsorbed, clearance
values are less than the GFR of 125-130 mL/min
• Many drugs are weak acids or bases, therefore the pH
of the filtrate can greatly influence the extent of
reabsorption for many drugs.
• The reabsorption of drugs that are acids or weak bases
is influenced by the pH of the fluid in the renal tubule
(ie, urine pH) and the pKa of the drug

• Both of these factors together determine the percentage of
dissociated (ionized) and undissociated (nonionized) drug.
• Generally, the undissociated species is:
 more lipid soluble (less water soluble)
 has greater membrane permeability, and hence
 easily reabsorbed from the renal tubule back into the body.
• This process of drug reabsorption can significantly reduce the
amount of drug excreted, depending on the PH of the urinary
fluid and the pKa of the drug.
• The pKa of the drug is a constant, but the normal urinary pH
may vary from 4.5-8 depending on diet, pathophysiology and
drug intake

• By far the most important changes in urinary pH are caused by
fluids administered intravenously( i.e. solutions of bicarbonate or
ammonium chloride)
• Excretion of these solutions may drastically change urinary pH
and alter drug reabsorption and drug excretion by the kidney
• The percentage of ionization of weak acid drug can be
determined by Handerson-Hasselbalch equation.

Where,
[A–] are the concentrations of the ionized form of the acid,
[HA] is the concentration of the unionized form, and vice versa
[𝐈]
[𝐔]

For weak acids
pH= pKa + log
Rearranging the above equation gives:
= 10pH-pKa
OR
[ionized]= 10pH-pKa[unionized]
As we know,
% of drug ionized=
Putting the value of [ionized] in above equation gives:

% of drug ionized=
=
% of drug ionized=

Similarly for weak bases:
pH= pKa+ log
OR

For example: Amphetamine
 It is a weak base, will be reabsorbed if urine pH is made
alkaline and more lipid soluble nonionized species are formed.
 In contrast, acidification of urine will cause the amphetamine
to become more ionized(form a salt).
The salt form is more water soluble, less likely to be absorbed, and tends to
be excreted into the urine more quickly.
For example: Salicylic acid
 It is a weak acids , acidification of the urine causes greater
reabsorption of the drug and alkalinization of the urine causes
more rapid excretion of the drug.
Hence weakly basic drugs will be reabsorbed rapidly if urine is
made alkaline and weakly acidic drugs will be reabsorbed
rapidly if urine is made acidic.

CALCULATION OF URINE
PLASMA RATIO
From the Handerson-Hasselbalch Eq. a conc. ratio for the distribution
of a weak acid or basic drug b/w urine and plasma may be derived.
For weak acids
For weak bases

To summarize, renal drug excretion is a composite of
 passive filtration at the glomerulus,
 active secretion in the proximal tubule and
 Passive/active reabsorption in the distal tubule.

FACTORS AFFECTING RENAL
DRUG EXCRETION
1) Molecular Weight (pc
property of drug)
2) Urine pH
3) GFR
4) Lipid solubility (pc property
of drug)
5) Protein binding
6) Pathological condition
7) Concurrent drug
administration
8) Age

1) MOLECULAR WT.
Drugs having mol.wt. less than or equal to 300 dalton are excreted by
kidneys
While those having mol. Wt. b/w 300-500 are eliminated by both
kidneys and bile
2) URINE pH
One of the most important factor affecting renal drug excretion
Acidification of urine promotes the reabsorption of weak acids(as being
in unionized form)
While promotes the excretion of weak bases as they are ionized in
acidic medium & ionized drug is more water soluble & will be excreted
more & vice versa

3) G.F.R.
If the glomerular filtration rate is high then excretion of drugs
which are excreted via glomerular filtration will be more but in case
of low GFR in disease conditions or due to any other reason will
decrease the rate of drug excretion
4) LIPID SOLUBILITY
Lipid soluble drugs are not excreted and remain in circulation while
water soluble drugs are much more rapidly excreted

5) PROTEIN BINDING
Protein bound drugs cannot cross glomerular capillaries & hence
excretion of protein bound drugs cannot occur through this process
However tubular secretion process of renal excretion does not
depend upon protein binding and protein bound drugs can be
excreted via tubular secretion b/c protein binding is reversible and
active secretion breaks the protein bound drugs
6) PATHOLOGICAL CONDITION
If renal function is impaired in case of disease then there is
decreased in elimination rate of drugs that usually undergo renal
excretion i.e. streptomycin, gentamicin

7) CONCURRENT DRUG ADMINISTRATION
Affects renal drug excretion of already administered drug eg
probenecid vs penecillin
8) AGE
In case of old age as renal function is impaired so elimination of
drug which are eliminated by kidney is also impaired
To determine Excretion, following parameters are used:
i) Clearance
ii) Elimination half life
iii) Elimination rate constant

RENAL CLEARANCE
Before moving to Renal
Clearance, we must know
what is Clearance ????

CLEARANCE
• Also known as systemic clearance or total body clearance
• It is defined as: volume of blood which is completely cleared of drug
per unit time.
• Clearance is the measure of the functional ability of substance to be
removed by eliminating organ.
• Clearance is pharmacokinetic term measuring drug elimination from
the body without identifying the mechanism or process involved
• Clearance considers the entire body as a single drug eliminating
system from which many unidentified elimination process may occur
UNITS
Volume/time (liters/hour; milliliters/minute), ml/min/kg, L/hr/kg

• If the drug has more than 1 route of elimination then, total
clearance is the sum of individual clearances:
CL T = CL renal + CL hepatic + CL n
OR CL T = CL renal + CL non-renal

Basic formulas to determine clearance:
Total clearance =
ClT = --------
where,
DE= amount of drug excreted, dDE/dt= drug elimination rate
1

• Drugs are usually eliminated from the body at rate which
is proportional to their plasma concentration.
• As 1st order elimination rate (dDE/dt) is equal to total drug in
body (kDB), hence
dDE/dt= kDB
as, DB=Vd* Cp
dDE/dt=k VdCp

• If we put the value of elimination rate in eq.1, we get
ClT= ---------
Where,
K = overall elimination rate constant (K = ke+ km)
Vd = volume of distribution
2

• This Equation shows that clearance is the product of k and Vd,
both of which are constants.
• As the plasma drug concentration decreases during elimination,
the rate of drug elimination decrease accordingly, but clearance
remains constant.
• Clearance is constant as long as rate of drug elimination is a 1st
order process.
• Clearance values are often normalized on a per kilogram body
weight basis, such as milliliters/minute per Kilogram.
• The clearance for an individual patient is estimated as the
product of the clearance per kilogram multiplied by the body
weight( Kg) of the patient.

EXAMPLE:
In case of Penicillin….
Plasma drug
concentration
(g/ml)
Elimination rate
(ug/min)
Clearance
(ml/min)
2 30 15
10 150 15

• As the elimination rate constant (k ) represents the sum total of all
the rate constant for drug elimination, including excretion and
biotransformation, ClT is the sum total of all the clearance
processes in the body, including clearance through kidney (renal
clearance), lungs, and liver(hepatic clearance).
Renal Clearance = ke VD
Lung Clearance = Kl VD
Hepatic Clearance = Km VD
Therefore,
Body Clearance = ke VD + Kl VD + Km VD
OR
Body Clearance = (Ke + Kl + Km) VD = K VD

CLEARANCE MODELS
a) Compartment model
b) Physiological model
c) Non-compartmental or Model independent approach

COMPARTMENT MODEL
• The calculation of clearance from k and Vd assumes a defined
model.
• Clearance is commonly used to describe 1st order drug
elimination from compartment model such as the one
compartment model in which the distribution volume and
elimination rate constants are well defined.
Total clearance =
ClT = --------
where,
1
a

• As 1st order elimination rate (dDE/dt) is equal to total drug in body
(kDB), hence
dDE/dt= kDB
as, DB=Vd* Cp
dDE/dt=k VdCp
• If we put the value of elimination rate in eq.1, we get
Body Clearance= ClT = k . Vd

PHYSIOLOGICAL /ORGAN DRUG
CLEARANCE
• Clearance may be calculated for any organ involved in the irreversible
removal of drug from the body.
• Physiological pharmacokinetic models are based on drug clearance
through individual organs or tissue groups.
• For any organ, Clearance may be defined as the fraction of blood
volume containing drug that flows through organ and eliminated of
drug per unit time.
• From definition, organ drug clearance is the product of the blood
flow (Q) to the organ and the extraction ratio (ER, the fraction of drug
excreted by the organ as drug passes through).
Cl = Q(ER) ------ (i)
b

• If the drug concentration in the blood (Ca) entering the organ is
greater than the drug concentration of blood (Cv) leaving the
organ ,then some of the drug has been extracted by the organ.
• The ER is given as:
ER =
𝑪𝒂 −𝑪𝒗
𝑪𝒂
-------- (ii)
• ER is a ratio with NO units.
• Values of ER range from 0-1
An ER of 0.25 indicates that 25% of the incoming drug conc. is
removed by the organ as the drug passes through it.

• Substituting for ER into equation (i)
Cl = Q (𝑪𝒂 −𝑪𝒗
𝑪𝒂
) ------- (iii)
• The physiologic approach to clearance shows that clearance
depends on the blood flow rate and the ability of the organ to
eliminate drug.
• However clearance measurements using the physiological
approach require invasive techniques to obtain measurement of
blood flow and extraction ratio.
• Mostly applied in case of hepatic clearance.

MODEL-INDEPENDENT
METHOD
• Model independent methods are non compartment model
approaches used to calculate certain pharmacokinetic parameters
such as clearance and bioavailability (F).
• The major advantage of model independent approach is that no
assumption for a specific compartment model is required to analyze
data.
• NO need to calculate k and Vd.
• In model independent approach, plasma level time curve is used for
calculation of clearance.
c

For example:
According to this approach, the total body clearance is estimated by
ClT =
Where,
Do= initial dose and [AUC]o
∞
= o∫ ∞ Cpdt
Because [AUC]o
∞
is calculated from the plasma drug conc.-time curve
from 0 to infinity using the trapezoidal rule, no compartmental model is
assumed.
This calculation of ClT is referred to as a non-compartment or model-
independent method.

RENAL DRUG CLEARANCE
• Renal clearance (ClR) is defined as:
“ the volume of plasma that is cleared of drug per unit
time through kidney.”

• More simply, it is defined as urinary excretion rate
(dDu/dt) divided by plasma concentration (Cp)
ClR =
=

• For any drug cleared through the kidney:
rate of drug passing through kidney = rate of drug excreted in
urine
i.e. ClR . Cp = Qu . Cu
ClR = Qu .
𝑪𝒖
𝑪𝒑
Where,
Qu = rate of urine flow
Cu = concentration of drug in urine
Also,
ClR = Qu .
𝑪𝒖
𝑪𝒑
=
𝑬𝒙𝒄𝒓𝒆𝒕𝒊𝒐𝒏 𝒓𝒂𝒕𝒆
𝑪𝒑
=

COMPARISON OF DRUG
EXCRETION METHODS (VIA
KIDNEY)
• From a physiologic viewpoint, however, renal clearance may be
considered as the ratio of the sum of the Glomerular filtration and
active secretion rates less the reabsorption rate divided by the
plasma drug concentration
Renal Clearance =

Clearance ratio Mechanism of excretion
Cldrug
Clinulin
< 1 Drug partially reabsorbed
Cldrug
Clinulin
= 1 Drug filtered only
Cldrug
Clinulin
> 1 Drug actively secreted
• In order to understand that through which process the drug
undergoes renal clearance, the ratio of renal clearance of drug to
that of inulin i.e. Clearance ratio is taken.

FILTERATION ONLY
• If glomerular filtration is the sole process for drug excretion and no
drug is reabsorbed, then amount of drug filtered at any time ,t, will
always be:
Cp . GFR
• If the ClR of the drug is by glomerular filtration only , then:
ClR = GFR
• Otherwise, ClR represents all the process by which drug is cleared
through the kidney, including any combination of filtration,
reabsorption and active secretion.

• If we compare the rate of drug excretion using a
compartment approach and physiological approach, we get:
or Clr = ke Vd
or
Clr
Vd
= ke
dDu/dt = ke . Vd . Cp dDu/dt = Clr . Cp
ke Vd . Cp = Clr . Cp
Above equation shows that , in the absence of other processes of
drug elimination, the excretion rate constant reflects the volume
pumped out per unit time due to GFR relative to the volume of body
compartment VD.

• For a drug with reabsorption fraction of ‘Fr’ the drug excretion rate
is reduced and equation is given as:
dDu/dt = Clr (1-Fr) Cp
FILTERATION &
REABSORPTION

FILTRATION AND ACTIVE
SECRETION
• For a drug that is primarily filtered and secreted, with negligible
reabsorption, the overall excretion rate will exceed GFR.
• At low drug plasma concentration, active secretion is not saturated
and drug is excreted by filtration and active secretion.
• At high concentrations, the percentage of drug excreted by active
secretion decreases due to saturation.

DETERMINATION OF RENAL
CLEARANCE
1. Graphical determination of Clr:
• The clearance is given by the slope of the curve obtained by
plotting the rate of drug excretion in urine (dDu/dt) against
Cp.
• For a drug that is excreted rapidly:
 (dDu/dt) is large, the slope is steeper.
• For a drug that is excreted slowly through the kidney:
 the slope is smaller.
Plasma
level (Cp)
Rate
of
drug
excretion
(dDu/dt)
Higher
Cl
Lower
Cl

From equation,
ClR =
𝑑𝐷𝑢/𝑑𝑡
𝐶𝑝
…………….. (1)
Multiplying both sides by Cp
ClR . Cp = 𝑑𝐷𝑢/𝑑𝑡 ………. (2)
By rearranging equation (2) and integrating
o∫Du dDu = ClR o∫t Cp dt
[Du]o
t
= ClR [AUC]o
t

• A graph is then plotted of cumulative drug excreted in the
urine ([Du]o
t
) versus the area under the concentration – time
curve ( [AUC]o
t
)
• Renal clearance is obtained from the slope of the curve.
• The area under curve can be estimated by the trapezoidal
rule.
• Disadvantage: if a data point is missing, the cumulative
amount of drug excreted in the urine is difficult to obtain.
• However, if the data are complete then the determination of
clearance is more accurate by this method.

2. Model-independent
methods
• Clearance rates may also be estimated by a single (nonographical)
calculation from [AUC]o- ∞ and the total amount of drug excreted in
the urine, Du ∞.
ClT = Do/[AUC]o- ∞
• If the total amount of drug excreted in the urine, Du ∞, has been obtained,
then renal clearance is calculated by
ClR=
Du ∞
[AUC]o− ∞

• Clearance can also be calculated from fitted parameters. ( i.e.
compartment model approach)
• If the volume of distribution and elimination constants are known,
body clearance (ClT), renal clearance (ClR), and hepatic clearance
(Clh) can be calculated according to the following expressions:
ClT= kVD (i)
ClR= keVD (ii)
Clh= kmVD (iii)

Total body clearance (ClT) is equal to the sum of renal clearance and
hepatic clearance i.e.
ClT= ClR+ Clh (iv)
By substitution equations (i) and (ii) into equation (iv),
kVD = keVD + kmVD (v)
Dividing by VD on the both sides of equation (v), we get
K= ke + km (vi)

RENAL CLEARANCE OF
PROTEIN BOUND DRUG
• Clearance of protein bound drugs ONLY occurs by active tubular
secretion and not by Glomerular filtration. Thus the relation;
Clr =
needs modification i.e. in place of Cp, we should use ONLY unbound
fraction of drug.
Clr =
However, for most drug studies, the total plasma drug concentration is
used in clearance calculations

RELATIONSHIP OF CLEARANCE
TO ELIMINATION HALF LIFE &
VOLUME OF DISTRIBUTION
The half life of a drug can be determined if the clearance and VD are
known.
We know
ClT = kVD (1)
as, K = 0.693/t1/2
Putting value in eq.1
ClT = 0.693VD/t1/2
t1/2=
0.693VD
ClT

• Thus, from above equation as Cl decreases (which might
happen in some renal diseases), t1/2 for the drug increases.
• Total body clearance , ClT is a more useful index of
measurement of drug removal as compared to the
elimination half life t1/2.
• Total body clearance , ClT takes into account changes in
both the apparent vol. of distribution, VD and the t1/2.

TOTAL BODY CLEARANCE
OF DRUG AFTER
INTRAVENOUS INFUSION
When drugs are administered by IV infusion, the total body clearance
is obtained with the following equation.
ClT =
𝑅
𝐶𝑠𝑠
Where;
Css is the steady state plasma drug concentration and
R is the rate of infusion.

SO…..
• The elimination of most drugs from the body involves the process
of both metabolism (biotransformation) and renal excretion.
• For many drugs, the principal site of metabolism is the liver.
• Drugs that are highly metabolized(such as phenytoin) often
demonstrate large inter subject variability in the elimination half
lives and are dependent on the intrinsic activity of the
biotransformation enzymes, which may vary by genetic and
environmental factors.

• Inter subject variability in elimination half lives is less
for drugs that are eliminated primarily by renal drug
excretion.
• Renal drug excretion is highly dependent on GFR and
blood flow to the kidney.
• Since GFR is relatively constant among individuals
with normal renal function, the elimination of drugs
that are primarily excreted unchanged in the urine is
also less variable.

HEPATIC CLEARANCE
‘Volume of blood perfuses the liver and is cleared of drug per unit time’
Hepatic clearance (Clh) is also equal to total body clearance (ClT) minus
renal clearance (ClR) as follows:
Clh = ClT -ClR --------
If blood flow (Q) and extraction ratio (ER) are determinable, then hepatic
clearance can be calculated as:
Clh= Q . ER --------
Where,
Q= blood flow to liver, ER= extraction ratio= Ca-Cv/Ca
Ca= conc. of drug in artery, Cv = conc. of drug in vein
1
2

• If ER=1:
 then the rate limiting step in hepatic clearance is the hepatic
blood flow, and hepatic clearance is almost equal to the
hepatic blood flow. i.e. Clh= Q
 In above case, Clh is less affected by fraction of drug protein
binding.
• In contrast, if ER is very less:
 then Clh is affected by drug protein binding and the intrinsic
activity of liver to eliminate the drug. (as only unbound fraction
of drug is capable of permeation) and is not affected by
hepatic blood flow.

If intrinsic clearance (Clint) and fraction unbound in plasma
(fu) are known, then hepatic clearance can be calculated as:
Clh= Clint . Fu
Intrinsic clearance:
It is the ability of liver to remove drug from blood in the
absence of confounding factors (blood flow, drug-protein
binding)
It can be calculated by the ratio of Michales-Menten
parameters:
Clint =
𝒗𝒎𝒂𝒙
𝒌𝑴
𝒗𝒎𝒂𝒙 = max. velocity
of metabolic
reaction
𝒌𝑴 = ½ 𝒗𝒎𝒂𝒙
= conc. of drug
which shows ½ 𝒗𝒎𝒂𝒙
reaction
--------
3

% OF DRUG METABOLIZED
Because these rates of elimination at low drug concentration are
considered first-order processes, the percentage of total drug
metabolized may be obtained by the following expression:
Similarly, in case of renal excretion:
Km =
Metabolism
rate constant
Ke =
Excretion
rate constant
K=
elimination
rate constant

FRACTION OF DRUG EXCRETED
UNCHANGED (fe)
&
FRACTION OF DRUG
METABOLIZED (1-fe)
For many drugs, the literature has approximate values for the fraction of
drug (fe) excreted unchanged in the urine
For most drugs, the fraction of dose eliminated unchanged (fe) and the
fraction of dose eliminated as metabolites (1-fe) can be determined using
formulas:
4
--------

SOLVE ME
The total body clearance of a drug is 10 mL/ min/kg. The renal
clearance is not known. From a urinary drug excretion study, 60% of
the drug is recovered intact and 40% is recovered as metabolites.
What is the hepatic clearance for the drug, assuming that metabolism
occurs in the liver?

ANSWER
Hepatic clearance = total body clearance × (1 – fe)
(12.7)
where fe = fraction of intact drug recovered in the urine.
Hepatic clearance = 10 × (1 – 0.6) = 4 mL/min/kg
In this example, the metabolites are recovered completely and
hepatic clearance may be calculated as total body clearance times the
percent of dose recovered as metabolites. Often, the metabolites are
not completely recovered, thus precluding the accuracy of this
approach.

EXTRAHEPATIC METABOLISM
A few drugs (eg, nitroglycerin) are metabolized extensively
outside the liver. This is known as extrahepatic metabolism.
A simple way to assess extrahepatic metabolism is to calculate
hepatic (metabolic) and renal clearance of the drug and
compare these clearances to total body clearance.

SOLVE ME
Morphine clearance, ClT, for a 75-kg male patient is 1800
mL/min. After an oral dose, 4% of the drug is excreted
unchanged in the urine (fe = 0.04). The fraction of drug
absorbed after an oral dose of morphine sulfate is 24% (F =
0.24). Hepatic blood flow is about 1500 mL/min. Does
morphine have any extrahepatic metabolism?

ANSWER
Since fe = 0.04
nonrenal clearance Clnr = (1 – 0.04) ClT = 0.96 ClT. Therefore, Clnr
= 0.96 × 1800 mL/min = 1728 mL/ min.
Since hepatic blood flow is about 1500 mL/ min, the drug appears to
be metabolized faster than the rate of hepatic blood flow. Thus, at
least some of the drug must be metabolized outside the liver.
The low fraction of drug absorbed after an oral dose indicates that
much of the drug is metabolized before reaching the systemic
circulation

FIRST PASS EFFECT
For some drugs, the route of administration affects the metabolic rate
of the compound.
For example, a drug given parenterally, transdermally, or by
inhalation may distribute within the body prior to metabolism by the
liver.
In contrast, drugs given orally are normally absorbed in the duodenal
segment of the small intestine and transported via the mesenteric
vessels to the hepatic portal vein and then to the liver before entering
the systemic circulation.
Drugs that are highly metabolized by the liver or by the intestinal
mucosal cells demonstrate poor systemic availability when given
orally.

FIRST PASS EFFECT
The rapid metabolism of an orally administered drug prior to
reaching the systemic circulation is known as first pass effect or
presystemic elimination.
Or
Enzymatic degradation of orally administered drug prior
reaching to systemic circulation is called first pass effect.

Sites:
- Liver
oThe liver is the most important site of pre-systemic elimination because of:
a) Its high level of drug metabolizing enzyme
b) Its ability to rapidly metabolize many different kinds of drug molecules
c) Its anatomic location and blood supply
Drugs undergoing first pass metabolism:
Β-blockers: E.g. propranolol, metoprolol Analgesics: E.g. meperidine,
propoxyphene
Antidepressants: E.g. imipramine, nor-tryptyline Antiarrythmics: E.g. Lidocaine,
verapamil

EVIDENCE OF FIRST PASS
METABOLISM
….When there is lack of parent drug in the systemic circulation, first pass effect is
suspected….
The evidence for this is provided by:
1) AUC
In case of first pass metabolism, AUC for orally administered drug is less than
the AUC for IV administered drug.
2) From experimental findings in animals, first-pass effects may be assumed if
the intact drug appears in a cannulated hepatic portal vein but not in general
circulation. Sampling of drug from the hepatic portal vein and artery is difficult and
performed mainly in animals only.
For an orally administered drug that is chemically stable in the gastrointestinal
tract and is 100% systemically absorbed (F = 1), the area under the plasma
drug concentration curve, AUC 0.oral should be the same when the same drug
dose is given intravenously, AUC 0.IV.
3) Absolute Bioavailability (F)
It also indicates the degree of first pass effect undergone by drugs
F= [AUC]PO/DosePO

• For drugs undergoing first pass effect the value of F is less than 1 and AUC
oral < AUC IV. Eg, nitroglycerine, morphine and propranolol.
4) Liver extraction ratio (E.R)
It is the estimate of the extent to which a drug is removed by the liver after
oral administration
Liver E.R = Ca-Cv/Ca
Where,
Ca = drug conc. entering the liver i.e. in arteries
Cv= drug conc. leaving the liver i.e. in veins
• Drugs with low ER have lower 1st pass effect after oral administration

LIVER EXTRACTION RATIO
Because there are many other reasons for a drug to have a reduced F
value, the extent of first-pass effects is not precisely measured from
the F value.
The liver extraction ratio (ER) provides a direct measurement of drug
removal from the liver after oral administration of a drug.
E.R = Ca-Cv/Ca
Ca = drug conc. entering the liver i.e. in arteries
Cv= drug conc. leaving the liver i.e. in veins
Because Ca is usually greater than Cv, ER is usually less than 1.
For example, for propranolol, ER or [E] is about 0.7 ie, about 70% of
the drug is actually removed by the liver before it is available for
general distribution to the body.

LIVER EXTRACTION RATIO
By contrast, if the drug is injected intravenously, most of the drug
would be distributed before reaching the liver, and less of the drug
would be metabolized the first time the drug reaches the liver.
The ER may vary from 0 to 1.0. An ER of 0.25 means that 25% of the
drug is removed by the liver.
If both the ER for the liver and the blood flow to the liver are known,
then hepatic clearance, Clh, may be calculated by the following
expression:
Clh= Q . ER = Q (Ca – Cv) / Ca

METHODS TO OVERCOME
FIRST PASS EFFECT
1) Change the route of administration i.e. avoid oral route e.g.
Nitroglycerine sublingually, xylocaine may be given
parenterally to avoid the first-pass effects.
2) Administer in large doses
3) Change to rapidly absorbable dosage form

SIGNIFICANCE OF FIRST
PASS EFFECT
1) Pro-drugs are generally inactive unless they are converted into their
parent compounds by metabolism e.g. Becampicillin  Ampicillin
2) Many anticancer drugs are first converted to their active metabolite and
then exert their action e.g. cyclophosphamide & isophosphamide 5-
flurouracil
3) Decreased concentration of parent drug in systemic circulation
4) Decreased therapeutic response of the drug
5) Dose adjustment

RELATIONSHIP BETWEEN
ABSOLUTE BIOAVAILABILITY
AND LIVER EXTRACTION
The following relationship between bioavailability and liver extraction
enables a rough estimate of the extent of liver extraction:
F = 1 - ER - F″
where F is the fraction of bioavailable drug
ER is the drug fraction extracted by the liver
F″ is the fraction of drug removed by nonhepatic process prior to
reaching the circulation.
If F″ is assumed to be negligible ie, there is no loss of drug due to
chemical degradation, gut metabolism, and incomplete absorption,
ER may be estimated from:
F = 1 – ER

ABSOLUTE BIOAVAILABILITY
AND LIVER EXTRACTION
Substituting the formula of F in the above equation we get:-
ER is a rough estimation of liver extraction for a drug. Many other factors may alter
this estimation: the size of the dose, the formulation of the drug, and the
pathophysiologic condition of the patient all may affect the ER value obtained. if an
oral drug product has slow dissolution characteristics or release rate, then more of
the drug will be subject to first-pass effect compared to doses of drug given in a
more bioavailable form.
Liver ER provides valuable information in determining the oral dose of a drug when
the intravenous dose is known. For example, propranolol requires a much higher
oral dose compared to an IV dose to produce equivalent therapeutic blood levels,
because of oral drug extraction by the liver.
Liver extraction is affected by blood flow to the liver.

ESTIMATION OF REDUCED
BIOAVAILABILITY DUE TO LIVER
METABOLISM AND VARIABLE
BLOOD FLOW
Blood flow to the liver plays an important role in the amount of drug metabolized
after oral administration. Changes in blood flow to the liver may substantially alter
the percentage of drug metabolized and therefore alter the percentage of
bioavailable drug. The relationship between blood flow, hepatic clearance, and
percent of drug bioavailable is:
Clh is the hepatic clearance of the drug
Q is the effective hepatic blood flow
F′ is the bioavailability factor obtained from estimates of liver blood flow and
hepatic clearance, ER.
This equation provides a reasonable approach for evaluating the reduced
bioavailability due to first-pass effect.
The usual effective hepatic blood flow is 1.5 L/min, but it may vary from 1 to 2
L/min depending on diet, food intake, physical activity, or drug intake

ESTIMATION OF REDUCED
BIOAVAILABILITY DUE TO LIVER
METABOLISM AND VARIABLE
BLOOD FLOW
Presystemic elimination or first-pass effect is a very important
consideration for drugs that have a high extraction ratio.
Drugs with high presystemic elimination tend to demonstrate
more variability in drug bioavailability between and within
individuals.
The quantity and quality of the metabolites formed may vary
according to the route of drug administration, which may be
clinically important if one or more of the metabolites has
pharmacologic or toxic activity.
Drugs with low extraction ratios, such as theophylline, have
very little presystemic elimination.

BLOOD FLOW, INTRINSIC
CLEARANCE, AND HEPATIC
CLEARANCE
 Factors that affect the hepatic clearance of a drug include :-
1. Blood flow to the liver
2. Intrinsic clearance
3. Fraction of drug bound to plasma protein

 BLOOD FLOW TO THE
LIVER
A change in liver blood flow may alter hepatic clearance and F′. A large
blood flow may deliver enough drug to the liver to alter the rate of
metabolism. In contrast, a small blood flow may decrease the delivery of
drug to the liver and become the rate-limiting step for metabolism. The
hepatic clearance of a drug is usually calculated from plasma drug data
rather than whole-blood data.
Hepatic clearance can be calculated by equation
Clh= Q . ER
Where,
Q= blood flow to liver
ER= extraction ratio= Ca-Cv/Ca
Ca= conc. of drug in artery
Cv = conc. of drug in vein
This indicates that clearance is directly proportional to blood flow

HIGH EXTRACTION RATIO
DRUGS
• For some drugs such as isoproterenol, lidocaine and nitroglycerine
the extraction ratio is high (>0.7) and drug is removed by the liver
almost as rapidly as the organ is perfused
• For drugs with very high extraction ratios, the rate of drug
metabolism is sensitive to changes in hepatic blood flow. Thus, an
increase in blood flow to the liver will increase the rate of drug
removal by the organ.
• Propranolol, a beta-blocker decreases the hepatic blood flow by
decreasing cardiac output and thus decreases its own clearance
through the liver.

 INTRINSIC CLEARANCE
• It is used to describe the total ability of the liver to metabolize the drug
in the absence of flow limitation reflecting the inherent activities of the
mixed function oxidases and all other enzymes.
• Intrinsic clearance is a distinct characteristic of a particular drug.
• Intrinsic clearance may be shown to be analogous to the ratio Vmax/KM
for a drug that follows Michaelis–Menten kinetics. Hepatic clearance is a
concept for characterizing drug elimination based on both the blood flow
and the intrinsic clearance of the liver as shown below:
• Clh= Q .
Clint
Q + Clint

LOW EXTRACTION RATIO
DRUGS
Hepatic clearance changes with blood flow and the intrinsic clearance.
Hepatic clearance of drugs with low extraction ratio are more affected
by the intrinsic activity of mixed function oxidases than the hepatic
blood flow e.g. theophylline, phenylbutazone and procainamide
Clearance to be estimated when physiologic or disease conditions
cause changes in blood flow or intrinsic enzyme activity. Smoking, for
example, can increase the intrinsic clearance for the metabolism of
many drugs.
Changes or alterations in mixed-function oxidase activity or biliary
secretion can affect the intrinsic clearance and thus the rate of drug
removal by the liver.
Drugs that show low extraction ratios and are eliminated primarily by
metabolism demonstrate marked variation in overall elimination half-
lives within a given population.

LOW EXTRACTION RATIO
DRUGS
For example, the elimination half-life of theophylline varies from 3 to 9
hours. This variation in t ½ is thought to be due to genetic differences in
intrinsic hepatic enzyme activity. Moreover, the elimination half-lives of
these same drugs are also affected by enzyme induction, enzyme
inhibition, age of the individual, nutritional, and pathologic factors.
Clearance may also be expressed as the rate of drug removal divided by
plasma drug concentration
The rate of drug removal by the liver is usually the rate of drug
metabolism

HEPATIC CLEARANCE OF
PROTEIN BOUND DRUGS:
RESTRICTIVE AND NON
RESTRICTIVE CLEARANCE
FROM BINDING
They are assumed to be of two types:
a) Restrictively cleared drug:
• Also known as binding sensitive
• Extraction ratio is less
• Bound drugs are not able to diffuse through cell membrane & thus not
able to reach the site of metabolism, while free (unbound) drugs can
reach the site of MFOs and are subjected to metabolism.
• For restrictively cleared drugs, change in binding generally alters drug
clearance
• Thus for such drugs increase in free drug concentration in the blood
will make more drug available for hepatic extraction.

RESTRICTIVE AND NON
FROM BINDING
b) Non restrictively eliminated drugs:
Examples are propranolol, morphine, and verapamil.
These are extracted by the liver regardless of drug bound to protein
or free.
A drug is nonrestrictively cleared if its hepatic extraction ratio (ER) is
greater than the fraction of free drug (fu), and the rate of drug
clearance is unchanged when the drug is displaced from binding.
The protein binding of a drug is a reversible process and for a
nonrestrictively bound drug, the free drug gets “stripped” from the
protein relatively easily compared to a restrictively bound drug during
the process of drug metabolism
The elimination half-life of a nonrestrictively cleared drug is not
significantly affected by a change in the degree of protein binding.

RESTRICTIVE AND NON
FROM BINDING
For a drug with restrictive clearance, the relationship of blood flow
follows
Clh=Q .
Fu Cl′int
Q + Fu C′lint
fu is the fraction of drug unbound in the blood and Cl’int is the
intrinsic clearance of free drug.
When Cl’int is very small in comparison to hepatic blood flow then
above equation reduces to
Clh= Q .
Fu Cl′int
Q
Or
Clh= fu.Cl’int

RESTRICTIVE AND NON
FROM BINDING
For a drug having very high Cl’int, in comparison to flow i.e.
Cl’int>>Q, the equation becomes
Clh= Q .
Fu Cl′int
Fu Cl′int
i.e. Clh=Q
Thus for drugs with a very high Clint=Clh depends on hepatic blood
flow and independent of protein binding.

DRUG BIOTRANSFORMATION
REACTIONS
The hepatic biotransformation enzymes play an important role in the
inactivation and subsequent elimination of drugs that are not easily
cleared through the kidney.
For most biotransformation reactions, the metabolite of the drug is
more polar than the parent compound. This enables the drug to be
eliminated more quickly.
A lipid-soluble drug crosses cell membranes and is easily reabsorbed
by the renal tubular cells, exhibiting a consequent tendency to remain
in the body.
In contrast, the more polar metabolite does not cross cell membranes
easily, is filtered through the glomerulus, is not readily reabsorbed,
and is more rapidly excreted in the urine.

REACTIONS
The nature of the drug and the route of administration may influence
the type of drug metabolite formed.
For example, isoproterenol given orally forms a sulfate conjugate in
the gastrointestinal mucosal cells, whereas after IV administration, it
forms the 3-O-methylated metabolite via S-adenosylmethionine and
catechol-O-methyltransferase.
Azo drugs such as sulfasalazine are poorly absorbed after oral
administration. However, the azo group of sulfasalazine is cleaved by
the intestinal microflora, producing 5-aminosalicylic acid and
sulfapyridine, which is absorbed in the lower bowel.
The biotransformation may be classified according to the
pharmacologic activity of the metabolite or according to the
biochemical mechanism for each biotransformation reaction. For
most drugs, biotransformation results in the formation of a more
polar metabolite(s) that is pharmacologically inactive and is

REACTIONS
The metabolite may be pharmacologically active or produce toxic
effects.
Prodrugs are inactive and must be biotransformed in the body to
metabolites that have pharmacologic activity. Prodrugs are designed
to improve drug stability, increase systemic drug absorption, or to
prolong the duration of activity.
For example, the antiparkinsonian agent levodopa crosses the blood–
brain barrier and is then decarboxylated in the brain to l-dopamine,
an active neurotransmitter. l-Dopamine does not easily penetrate the
blood–brain barrier into the brain and therefore cannot be used as a
therapeutic agent

SITES OF BIOTRANSFORMATION
Liver
• The primary site for metabolism of almost all drugs because it is
relatively rich in a large variety of metabolizing enzymes.
• Metabolism by organs other than liver (called as extra-hepatic
metabolism) is of lesser importance because lower level of metabolizing
enzymes is present in such tissues.
• Within a given cell, most drug metabolizing activity is found in the
smooth endoplasmic reticulum, SER and the cytosol.
• Drug metabolism can also occur in mitochondria, nuclear envelope and
plasma membrane.
• A few drugs are also metabolized by non-enzymatic means called as
non-enzymatic metabolism. For example, atracurium, (a neuromuscular
blocking drug)

OTHER SITES OF
BIOTRANSFORMATION..CONT.
Cutaneous tissues
• Epidermis can carry out several metabolic reaction including
glucuronide conjugation
• There are evidences of cutaneous metabolism of adrenal steroids,
hydrocortisone and flurouracil
• Vidarabine (an antiviral agent) has cutaneous metabolism.
• First pass drug metabolism in skin reduces the duration and
potency of locally applied drugs

Gastrointestinal tract
• Drugs can be conjugated by various enzymes in intestinal
epithelium and consequently this presystemic metabolism
cause an incomplete bioavailability of drugs.
• Presystemic metabolism of premarin in gastrointestinal tract is
example.
Lungs
• Lung are perfused by entire blood supply and the drug in
blood is presented to enzymes in lungs for metabolism
• A few drugs are prone to be metabolized in lungs.

Kidneys
• Some drugs are converted to their metabolites in
kidney by the action of angiotensin convertase
enzyme(ACE).
Brain
• A few drugs are metabolized in brain
e.g. Levodopa is converted into dopamine (active form)

SUB-CELLULAR LOCATIONS OF
METABOLIZING ENZYMES
1. ENDOPLASMIC RETICULUM (microsomes): the primary location for the
metabolizing enzymes.
(a) Phase I: cytochrome P450, flavin-containing monooxygenase,
aldehydeoxidase, carboxylesterase, epoxide hydrolase, prostaglandin
synthase, esterase.
(b) Phase II: uridine diphosphate-glucuronosyltransferase, glutathione S-
transferase, amino acid conjugating enzymes.
2. CYTOSOL (the soluble fraction of the cytoplasm): many water-soluble
enzymes.
(a) Phase I: alcohol dehydrogenase, aldehyde reductase, aldehyde
dehydrogenase, epoxide hydrolase, esterase.
(b) Phase II: sulfotransferase, glutathione S-transferase, N-acetyl transferase,
catechol 0-methyl transferase, amino acid conjugating enzymes.

3. MITOCHONDRIA. (power house of the cell; generates ATP)
(a) Phase I: monoamine oxidase, aldehyde dehydrogenase, cytochrome P450.
(b) Phase II: N-acetyl transferase, amino acid conjugating enzymes.
4. LYSOSOMES.
Phase I: peptidase.
5. NUCLEUS.
Phase II: uridine diphosphate-glucuronosyltransferase (nuclear membrane of
enterocytes).

• A number of enzymes in animals are capable of metabolizing
drugs. These enzymes are located mainly in the liver, but may
also be present in other organs like lungs, kidneys, intestine,
brain, plasma, etc.
• Majority of drugs are acted upon by relatively non-specific
enzymes, which are directed to types of molecules rather than
to specific drugs.
• The drug metabolizing enzymes can be broadly divided into
two groups:
1) Microsomal enzymes
2) Non-microsomal enzymes.
DRUG METABOLIZING
ENZYMES

Microsomal enzymes:
• The endoplasmic reticulum (especially smooth endoplasmic
reticulum) of liver and other tissues contain a large variety
of enzymes, together called microsomal enzymes
• (microsomes are minute spherical vesicles derived from
endoplasmic reticulum after disruption of cells by
centrifugation, enzymes present in microsomes are called
microsomal enzymes).
• They catalyze glucuronide conjugation, most oxidative
reactions, and some reductive and hydrolytic reactions.
• The monooxygenases, glucuronyl transferase, etc are
important microsomal enzymes.

Non-microsomal enzymes:
• Enzymes occurring in organelles/sites other than
endoplasmic reticulum (microsomes) are called non-
microsomal enzymes.
• These are usually present in the cytoplasm, mitochondria,
etc. and occur mainly in the liver, Gl tract, plasma and other
tissues.
• They are usually non-specific enzymes that catalyse few
oxidative reactions, a number of reductive and hydrolytic
reactions, and all conjugative reactions other than
glucuronidation.

Hepatic microsomal enzymes
(oxidation, conjugation)
Extrahepatic microsomal enzymes
(oxidation, conjugation)
Hepatic non-microsomal enzymes
(acetylation, sulfation,GSH,
alcohol/aldehyde dehydrogenase,
hydrolysis, ox/red)
DRUG METABOLISM

HEPATIC
BIOTRANSFORMATION
It is the conversion of a drug to its metabolites. These metabolites can be
inactive, active having activity as their parent drug or having different
activities. The metabolites are more excretable from the body.
The pathway of drug biotransformation is divided into two major groups of
reactions:
1 Phase I metabolism (asynthetic reactions )
2 Phase II metabolism (synthetic reactions )
A drug may be exposed to both of the reactions mentioned above and their
consequences may be illustrated as following.

prodrug Active drug
Polar
metaboli
te
Renal
or
biliary
excreti
on
Phase I reactions
Active
metabolite
s
Inactive
metabolites
Phase II
reactions
Conjugated
derivatives
Renal or
biliary
excretion

PHASE I METABOLIC REACTIONS
• Also known as non-synthetic reactions or functionalization
reactions
• Phase I reactions usually occur first and involve a change in drug
molecule by non-synthetic reactions such as:
 Oxidation
 Reduction
 Hydrolysis

SIGNIFICANCE
• In these reactions, a functional group is either introduced or
exposed on the drug molecule so as it can be attacked by phase II
enzymes.
• Group induction or exposure on a molecule in phase I reactions
lead to the increased polarity.
• The resulting product of phase I reaction is susceptible to phase
II reactions.

PHASE-I METABOLIC
REACTIONS
For example, oxygen is introduced into the phenyl group on
phenylbutazone by aromatic hydroxylation to form oxyphenbutazone,
a more polar metabolite.
Codeine is demethylated to form morphine.
The hydrolysis of esters, such as aspirin or benzocaine, yields more
polar products, such as salicylic acid and p-aminobenzoic acid,
respectively
For some compounds, such as acetaminophen, benzo[a]pyrene, and
other drugs containing aromatic rings, reactive intermediates, such as
epoxides, are formed during the hydroxylation reaction. These
aromatic epoxides are highly reactive and will react with
macromolecules, possibly causing liver necrosis (acetaminophen) or
cancer (benzo[a]pyrene).
Salicylic acid is also conjugated directly (phase II reaction) without a

PHASE I REACTIONS includes….
OXIDATION :
•Oxidative reactions are most important metabolic reactions, as
energy in animals is derived by oxidative combustion of organic
molecules containing carbon and hydrogen atoms.
• The oxidative reactions are important for drugs because they increase
hydrophilicity of drugs by introducing polar functional groups such as
-OH.

• The most important group of oxidative enzymes are microsomal
mono oxygenases or mixed function oxidases (MFO).
• These enzymes are located mainly in the hepatic endoplasmic
reticulum (ER) and require both molecular oxygen (02) and NADPH
to effect the chemical reaction.
• Mixed function oxidase name was proposed in order to characterise
the mixed function of the oxygen molecule, which is essentially
required by a number of enzymes located in the microsomes.

• The term monooxygenses for the enzymes was proposed as they incorporate
only one atom of molecular oxygen into the organic substrate with
concomitant reduction of the second oxygen atom to water.
• The most important component of mixed function oxidases is the
cytochrome P-450 because it binds to the substrate and activates oxygen.
• The wide distribution of cytochrome P-450 containing MFOs in varying
organs makes it the most important group of enzymes involved in the
biotransformation of drugs.

The several oxidation reactions occurring in body are:
1. Oxidation of alkyl chain:
Alkyl compounds, or alkyl side chains of the aromatic drugs with carboxyl,
aldehyde or amino group undergo oxidation. Examples include:
CH3-CH2-OH CH2-C-OH CH2-COOH

2. Oxidation of aromatic ring
NH-CO-CH3
OH
NH-CO-CH3
Acetanilide Acetaminoph
en
oxidation

Nitrosobenze
ne
Oxidation
Aniline
NH2
3. N-oxidation
NO2

4. Sulfoxidation
S
N
CH3
CH3
CH2-CH2-CH2-N
S
N
CH3
CH3
CH2-CH2-CH2-N
O
Chlorpromaz
ine
Chlorpromazine
sulfoxide
oxidati
on

5. Oxidative deamination
N
CH2-CH2-NH2
N
CH2-C-OH
O
oxidati
on
5-OH
Tryptamine
5-OH Indolacetic
acid
OH OH

6. Oxidative dealkylation
NH-CO-CH3
O-CH-CH3
oxidati
on
NH-CO-CH3
OH
Phenacetin P-
Acetaminophenol

• Both Microsomal as well as non-microsomal enzymes are
involved in oxidation reactions.
• Hydroxylation of aromatic ring, aliphatic hydroxylation,N-
oxidaton and sulfoxidation are the reactions catalysed by
microsomal enzymes.
• Whereas, dehydrogenation of ethyl alcohol into acetaldehyde,
conversion of hypoxanthine to xanthine, xanthine to uric acid
and tyrosine to dopa are catalysed by nonmicrosomal oxidases.

REDUCTION :
Reduction is less common than the oxidation and occurs in both, microsomal as well
as in nonmicrosomal metabolizing systems
These include:
1. N-Reduction
NO2 NH2
nitrobenzen
e aniline

2. Ketone reduction
CO.CH3 CH2OH
Acetopheno
ne
1 Phenyl
ethanol

CO-O-CH2-CH2-N
C2H5
C2H5
NH2
OH-CH2-CH2-N
C2H5
C2H5
NH2 COOH
+
Procaine Para-amino benzoic
acid
Diethylaminoetha
nol
HYDROLYSIS :
Also referred to as the replacement reaction and is indicated by enzyme esterases and amidases.
The examples of hydrolysis are:
1. Ester hydrolysis:
It yields alcohol and acid

2. Amide hydrolysis:-
It yields amine and acid
C- NH2
O
COOH
+
NH3
Benzami
de
Benzoic
acid

(CONJUGATION) PHASE II
REACTIONS
• Once a polar constituent is revealed or placed into the molecule, a phase II or conjugation
reaction may occur. Common examples include the conjugation of salicyclic acid with
glycine to form salicyluric acid or glucuronic acid to form salicylglucuronide.
• Phase II, synthetic or conjugation reactions may occur with the drug molecules with
exposed or induced polar constituent as a consequence of Phase I reactions
• The phase II reactions offer a mechanism whereby a functional group of a drug can be
blocked by addition of a conjugating agent.
• Since the outcome of such processes are generally products with increased molecular size
(and altered physicochemical properties) they are also called as synthetic reactions
• The conjugation reactions use conjugating reagents that are derived from the compounds
involved in carbohydrate, lipid, fat or protein metabolisms.
• The conjugating agents available for such reactions include Glucuronic acid, sulfate,
glycine, acetylCoA, glutathione.

REACTIONS
• Quite often, a phase I reaction may not yield a metabolite that is
sufficiently hydrophilic or pharmacologically inert but conjugation
reactions generally result in products with total loss of
pharmacologic activity and high polarity.
• Hence, phase II reactions are better known as true detoxification
reactions.
• Since these reactions generally involve transfer of moieties to the
substrate to be conjugated, the enzymes responsible are called as
transferases.

REACTIONS
Some of the conjugation reactions may have limited capacity at high
drug concentrations, leading to nonlinear drug metabolism.
In most cases, enzyme activity follows first-order kinetics with low
drug (substrate) concentrations. At high doses, the drug
concentration may rise above the Michaelis–Menten rate constant
(KM), and the reaction rate approaches zero order (Vmax).
Glucuronidation reactions have a high capacity and may demonstrate
nonlinear (saturation) kinetics at very high drug concentrations.
In contrast, glycine, sulfate, and glutathione conjugations show lesser
capacity and demonstrate nonlinear kinetics at therapeutic drug
concentrations.
The limited capacity of certain conjugation pathways may be due to
several factors, including (1) limited amount of the conjugate
transferase

•Glucuronidation and sulfate conjugation are very common phase II
reactions that result in water-soluble metabolites rapidly excreted in
bile and or urine.
•Acetylation and mercapturic acid synthesis are conjugation reactions
that are often implicated in the toxicity of drugs.
•Two schemes have been proposed for the phase II reactions.
•In scheme A, the conjugating agent, activated with energy combines
with the drug molecule in the presence of an appropriate drug
transferase enzyme to form the conjugate.
• In scheme B, a drug may be activated to a high energy compound to
react with a conjugating agent in the presence of the conjugating
agent transferase enzyme
• The schemes A and B, with examples can be illustrated in the following
figure:

Phase 2 reactions includes…
1. Glucuronidation
2. Sulfate conjugation
3. Acetylation
4. Methylation
5. Amino acid conjugation
6. Glutathione and mercaptopuric acid conjugation

The following are the phase II reactions along with examples:
1. Glucuronidation:
 Glucuronic acid conjugation is one of the most common route of drug
metabolism.
 Its significance lies in readily available supply of Glucuronic acid in liver
 The glucuronoid conjugates are pharmacologically inactive
 The reaction involves the condensation of drug with the activated form of
Glucuronic acid i.e. uridine diphosphate Glucuronic acid
 This reaction is catalyzed by glucuronyl transferase in liver

• Glucuronidation occurs for the drugs containing functional groups
OH, NH2, SH and COOH
These reactions include:
O-Glucuronidation
 Occurs by ester linkages with carboxylic acids
 Occurs by ether linkages with phenols and alcohols
Alcohol + glucuronide ether o glucuronide

N-glucuronidation:
 Occurs with amines (mainly aromatic )
 Occurs with amides and sulfonamides
+ Glucuronide
NH2
NH-C6H9O6
Aniline
N-
glucuronide

2. Sulfate conjugation
• The sulfate conjugation occurs in the drugs with functional groups of OH and
NH2.
• The high energy form of sulfate is 3’phosphoadenosin 5’ phosphosulfate (PAPS)
O-SO2-OH
OH
Pheno
l
Phenyl sulfuric
acid

3. Acetylation
• Acetylation occurs in the drugs with OH or NH groups
• Acetyl CoA is the high energy form of the conjugating agent
• Acetylated product is usually less polar than the parent drug and precipitate in sufficient concentration
in kidney tubules causing kidney damage and crystaluria.
• The less polar metabolite is reabsorbed in the renal tubule and has a longer elimination half-life. For
example, procainamide (t ½ = 3 to 4 hours) has an acetylated metabolite, N-acetylprocainamide, which
is biologically active and has an t ½ of 6-7 hour.
• The N-acetyltransferase enzyme responsible for catalyzing the acetylation of isoniazid and other drugs
demonstrates a genetic polymorphism. Two distinct subpopulations have been observed to inactivate
isoniazid, including the “slow inactivators” and the “rapid inactivators”. The former group may
demonstrate an adverse effect of isoniazid, such as peripheral neuritis, due to the longer elimination
half-life and accumulation of the drug.
• Acetylation is a conjugation reaction often implicated in the toxicity of the drug
• The drug metabolized by acetylation include sulfanilamide, sulfadiazine, procainamide and
sulfisoxazole.

3. Methylation
• The conjugating agent in methylation is CH3 from S-
adenosylmethionine (SAM)
• The functional group combined with this conjugating agents are
OH and NH2
• Nicotinamide N-methyl nicotinamide

4. Amino acid conjugation
• The amino acid conjugation uses the glycine as a conjugating agent
• The high energy form of this conjugating agent is the Coenzyme A thioesters
• In amino acid conjugation, the glycine combines with the drugs having functional
group COOH.
• The glycine conjugates are known as hippurates

5. Glutathione and Mercaptopuric acid
conjugation
• Glutathione (GSH)- a tripeptide of glutamyl-cysteine-glycine that is
involved in many important biochemical reactions.
• GSH is important in the detoxification of reactive oxygen intermediates into
nonreactive metabolites and is the main intracellular molecule for
protection of the cell.
• Through the nucleophilic sulfhydryl group of the cysteine residue, GSH
reacts nonenzymatically and enzymatically via the enzyme glutathione S-
transferase, with reactive electrophilic oxygen intermediates of certain
drugs.
• The resulting GSH conjugates are precursors for a group of drug conjugates
known as mercapturic acid (N-acetylcysteine) derivatives.
• The enzymatic formation of GSH conjugates is saturable.
• High doses of drugs such as acetaminophen may form electrophilic
intermediates and deplete GSH in the cell. These intermediate bind
covalently to hepatic cellular macromolecules, resulting in cellular injury

METABOLISM OF
ENANTIOMERS
Many drugs are given as mixtures of stereoisomers. Each isomeric form may
have different pharmacologic actions and different side effects.
For example, the natural thyroid hormone is l-thyroxine, whereas the
synthetic d enantiomer, d-thyroxine, lowers cholesterol but does not
stimulate basal metabolic rate like the l form.
Since enzymes as well as drug receptors demonstrate stereoselectivity,
isomers of drugs may show differences in biotransformation and
pharmacokinetics.
With improved techniques for isolating mixtures of enantiomers, many drugs
are now available as pure enantiomers.
The rate of drug metabolism and the extent of drug protein binding are
often different for each stereoisomer. (S)-(+)disopyramide is more highly

REGIOSELECTIVITY
Biotransformation enzymes may be regioselective. In this case, the
enzymes catalyze a reaction that is specific for a particular region in
the drug molecule.
For example, isoproterenol is methylated via catechol-O-
methyltransferase and S-adenosylmethionine primarily in the meta
position, resulting in a 3-O-methylated metabolite. Very little
methylation occurs at the hydroxyl group in the para position

GENETIC VARIATION OF
CYTOCHROME P-450 (CYP)
ISOZYMES
The most important enzymes accounting for variation in phase I metabolism of
drugs is the cytochrome P-450 enzyme group, which exists in many forms
among individuals because of genetic differences.
Initially, the cytochrome P-450 enzymes were identified according to the
substrate that was biotransformed. More recently, the genes encoding many of
these enzymes have been identified.
Multiforms of cytochrome P-450 are referred to as isozymes, and are classified
into families (originally denoted by Roman numerals: I, II, III, etc) and subfamilies
(denoted by A, B, C, etc) based on the similarity of the amino acid sequences of
the isozymes. If an isozyme amino acid sequence is 60% similar or more, it is
placed within a family. Within the family, isozymes with amino acid sequences of
70% or more similarity are placed into a subfamily, and an Arabic number follows
for further classification. The individual gene is denoted by an Arabic number
(last number) after the subfamily.
A new nomenclature starts with CYP as the root denoting cytochrome P-450, and
an Arabic number now replaces the Roman numeral.

ISOZYMES
The CYP3A subfamily of CYP3 appears to be responsible for the metabolism
of a large number of structurally diverse endogenous agents (eg,
testosterone, cortisol, progesterone, estradiol) and xenobiotics (eg,
nifedipine, lovastatin, midazolam, terfenadine, erythromycin). These are also
involved in the metabolism of vindesine, vinblastine, and other vinca
alkaloids.
The substrate specificities of the P-450 enzymes appear to be due to the
nature of the amino acid residues, the size of the amino acid side chain, and
the polarity and charge of the amino acids.
Cytochrome P-450 1A2 (CYP1A2) is involved in the oxidation of caffeine and
CYP2D6 (P-450IID6) is involved in the oxidation of drugs, such as codeine,
propranolol, and dextromethorphan. It is responsible for debrisoquine
metabolism which is polymorphic in the population, with some individuals
having extensive metabolism (EM) and other individuals having poor
metabolism (PM). Other drugs metabolized are flecainide, imipramine, and

ISOZYMES
There are now at least eight families of cytochrome isozymes known
in humans and animals.
CYP 1–3 are best known for metabolizing clinically useful drugs in
humans.
Variation in isozyme distribution and content in the hepatocytes may
affect intrinsic hepatic clearance of a drug. The levels and activities of
the cytochrome P-450 isozymes differ among individuals as a result
of genetic and environmental factors.

BIOACTIVATION
Generally biotransformation or metabolism produces more water
soluble chemical species and hence increase excretion. Thus toxicity
is reduced.
Bioactivation reactions are defined as biotransformation reactions
which lead to products with higher toxicity/activity than the parent
compounds.
Reactive compounds generated may be wither:-
Electrophiles (+):- these are deficient in electron pair and react with
nucleophilic groups in macromolecules such as DNA and proteins.
Or radicals (-) :- they contain odd number of electrons. Free radicals
produce toxicity by peroxidation. Protection against free radicals is
done by membrane structures neutralization by glutathione,
antioxidants ,eg, vitamin A,E,C and enzymatic inactivation of free
radicals.

CHRONOPHARMACOKINETIC
S AND TIME-DEPENDENT
PHARMACOKINETICS
Chronopharmacokinetics broadly refers to a temporal change in the
rate process (such as absorption or elimination) of a drug.
The temporal changes in drug absorption or elimination can be
cyclical over a constant period (eg, 24-hour interval), or they may be
noncyclical, in which drug absorption or elimination changes over a
longer period of time.
Time-dependent pharmacokinetics generally refers to a noncyclical
change in the drug absorption or drug elimination rate process over a
period of time. Time-dependent pharmacokinetics leads to nonlinear
pharmacokinetics. Time-dependent pharmacokinetics may be the
result of alteration in the physiology or biochemistry in an organ or a
region in the body that influences drug disposition.
Time-dependent pharmacokinetics may be due to autoinduction or
autoinhibition of biotransformation enzymes.

FACTORS AFFECTING
BIOTRANSFORMATION
(KULKARNI PG- 122-125)

TYPES OF FACTORS
1. Physicochemical properties of the drug
2. Chemical factors
a. Induction of drug metabolizing enzymes
b. Inhibition of drug metabolizing enzymes
c. Environmental chemicals

TYPES OF FACTORS
3. Biological factors:
a. Age
b. Gender
c. Genetics
d. Race
c. Diet
f. Altered physiologic factors:
 i. Pregnancy
 ii. Hormonal imbalance
 iii. Disease states
g. Temporal (time related) factor

1. PHYSICOCHEMICAL PROPERTIES
OF THE DRUG
• Just as the absorption and distribution of a drug are
influenced by drugs physicochemical properties, so
is its interaction with the drug metabolizing
enzymes.
• Molecular size and shape, pKa, acidity/basicity,
lipophilicity and electronic characteristics of a drug
influence its interaction with the active sites of
enzymes and the biotransformation processes to
which it is subjected.

2. CHEMICAL FACTORS
a. Induction of drug metabolizing
enzymes or enzyme induction
b. Inhibition of drug metabolizing
enzymes or enzyme inhibition
c. Environmental chemicals

A) ENZYME INDUCTION
• The phenomenon of increased drug metabolizing ability of the enzymes
(especially of microsomal monooxygenase system) by several drugs and
chemicals is called as enzyme induction and the agents which bring
about such an effect are known as inducers.
• Mechanism involved in enzyme induction may be
 increased enzyme synthesis,
 decreased rate of enzyme degradation,
 enzyme stabilization
 enzyme activation.
• Eg, alcohol, barbiturates, phenytoin, rifampin etc
• Auto induction/ self induction: The phenomenon in which a drug induces
their own metabolism. E.g. carbamazepine- antiepileptic.
Enzyme induction results in decreased pharmacologic activity of most
drugs and increased activity where the metabolites are active.

B) ENZYME INHIBITION
• Decrease in the drug metabolizing ability of enzymes.
• It can be of the following types:-
Competitive inhibition:- drugs compete with natural substrate for active site of an enzyme
due to structural similarity. It is reversible. Eg, succinylcholine inhibits acetylcholine esterase
by competing with acetylcholine.
Non competitive inhibition:- inhibitors are structurally not related to natural substrates. Eg,
enzyme inhibition by heavy metals.
Repression:- may be caused because of decreases synthesis or increased degradation of
enzyme.
• Enzyme inhibition generally results in prolonged pharmacologic action of a drug.

C) ENVIRONMENTAL
CHEMICALS
 Several environmental agents influence the drug metabolizing
ability of enzymes.
 Aromatic hydrocarbon contained in Cigarette smokers act as
enzyme inducers.
 Chronic alcoholism might lead to enzyme induction as well.
 Pesticides or Organophosphate insecticides may act as
enzyme inducers.
 At high altitude decreased biotransformation occurs due to
decreased oxygen leading to decreased oxidation of drugs.

3. BIOLOGICAL FACTORS
Age
Gender
Genetics
Race
Diet
Altered physiological factor
Temporal factors

A) AGE
Age dependent differences are due to differences in enzyme
content, enzyme activity and hemodynamics.
In infants:
Microsomal enzyme system is not fully developed.
The rate of metabolism is very low.
Chloramphenicol does not have great efficacy in infants. Toxic effects
in the form of grey baby syndrome might occur due to accumulation of
chloramphenicaol. Shock and even death might occur if toxic levels get
accumulated.

In elderly,
•most processes slow down which leads to
decreased metabolism.
•Decrease in liver functions and decreased
blood flow through the liver is common. All
these factors decrease the metabolism.
• The drug doses should be decreased in the
elderly

GENDER
Gender related differences in the rate of metabolism
are due to genetic control due to hormonal influence.
These are due to differences in enzyme concentration,
activities and changes in lipid environment of
enzymes.
Male have a higher BMR as compared to the females,
thus can metabolize drugs more efficiently, e.g.
salicylates and others might include ethanol,
propanolol, benzodiazepines.
b)

C) GENETIC DIFFERENCES
Differences among strains within the same species is also known.
A study of intersubject variability in drug response (due to differences in, for
example, rate of biotransformation) is called as pharmacogenetics.
Hence, drugs behave differently in different individuals due to genetic
variations
Succinyl choline, which is a skeletal muscle relaxant, is metabolized by pseudocholine
esterase. Some people lack this enzyme, due to which lack of metabolism of succinyl choline
might occur.

RACE/ SPECIES
 Asians, Blacks and Whites might have different
drug metabolizing capacity.
Examples include difference in drug metabolizing
capacity of certain anti malarial.
Ethnic variation is the difference observed in
metabolism of drug among different races due to
polymorphism.
In most European countries, approx. 40 %
population is fast acetylators and 96% of eskimos
are fast acetylators
Laboratory animals can metabolize drugs faster
than man e.g. barbiturates.
d)

DIET
The enzyme content and activity is altered by a
number of dietary components.
Low protein diet decreases and high protein
content in diet increases the drug metabolizing
ability.
Dietary deficiency of vitamins and minerals
retard the metabolic activity of enzymes.
e)

ALTERED PHYSIOLOGIC FACTORS
Pregnancy
Hormonal Imbalance
Disease states
f)

PREGNANCY
During pregnancy, metabolism of some drugs is
increased while that of others is decreased due to the
presence of steroid hormones e.g.
Phenytoin
Phenobarbitone
Pethidine

HORMONAL IMBALANCE
Higher levels of one hormone may inhibit the activity of
few enzymes while inducing that of others. E.g.
Antipyrine half-life shortened in case of
hyperthyroidism and prolonged during hypothyroidism

DISEASE STATES
Liver disease such as hepatic carcinoma, cirrhosis,
hepatitis, obstructive jaundice etc reduce the hepatic drug
metabolizing ability and thus increase the half lives of
almost all drugs.
In renal diseases conjugation of salicylates, oxidation of
vitamin D and hydrolysis of Procaine are impaired.
Cardiovascular diseases, although have no direct effect,
decrease the blood flow, which may slow
down biotransformation of drugs like isoniazid, morphine
and propanolol.
Pulmonary conditions may decrease biotransformation.
Procaine and procainamide hydrolysis is impaired.

TEMPORAL FACTOR
 Diurnal variations and variations in enzyme activity with light cycle is circadian
rhythm.
 The study of variations in drug response as influenced by time is called as
chronopharmacology.
 Time dependent change in drug kinetics is known as chronokinetics.
 Enzyme action is maximum during early morning and minimum in late afternoon
which is probably due to high and low levels of coticosterone.
 Drugs such as aminopyrine, hexobarbital and imipramine showed diurnal
variations in rats.
g)

ROUTE OF ADMINISTRATION
Oral route can result in extensive hepatic metabolism of some
drugs (first pass effect).
Lignocaine is almost completely metabolized if taken by oral
route therefore the preferable route is Topical.

BILIARY EXCRETION OF
DRUGS
• Irreversible transfer of drug or drug
metabolites from the plasma to the bile
through the hepatocytes is called biliary
excretion or biliary clearance
• Anatomy:- The intrahepatic bile ducts join
outside the liver to form the common hepatic
duct. The hepatic duct, containing hepatic bile,
joins the cystic duct that drains the gallbladder
to form the common bile duct. The common
bile duct then empties into the duodenum.
• Composition:- Bile primarily consists of water,
bile salts, bile pigments, electrolytes, & to a
lesser extent, cholesterol and fatty acids.
• The hepatic cells lining the bile canaliculi are
responsible for the production of bile. The

DRUGS
A drug to be excreted by bile must have following properties:
 Molecular weight:
 Mol wt > 500 Da excreted via bile
 Mol wt < 300 excreted via kidney
 Mol wt b/w 500 & 300 via both
 Must be highly polar such as metabolic conjugates.
Glucuronidation etc (Formation of glucuronide conjugates
increases mol. Wt by 200)
Examples of drugs excreted via bile are:
Digitalis glycosides, Bile salts, Cholesterol, Steroids, indomethacin
The efficacy of drug excretion by the biliary system can be tested
by an agent that is exclusively and completely eliminated unchanged
in the bile, e.g. sulfo-bromo-phthalein.

DRUGS
Compounds that enhance bile production stimulate the biliary
excretion of drugs normally eliminated by this route.
Eg, phenobarbital, which induces many mixed-function oxidase
activities, may stimulate the biliary excretion of drugs by two
mechanisms: by an increase in the formation of the glucuronide
metabolite and by an increase in bile flow.
In contrast, compounds that decrease bile flow or pathophysiologic
conditions that cause cholestasis, decrease biliary drug excretion.
The route of administration may also influence the amount of the
drug excreted into bile. For example, drugs given orally may be
extracted by the liver into the bile to a greater extent than the same
drugs given intravenously.

ESTIMATION OF BILIARY
CLEARANCE

ENTEROHEPATIC
CIRCULATION
 A drug or its metabolite is secreted into bile and upon
contraction of the gallbladder is excreted into the
duodenum via the common bile duct.
 From intestine the drug or its metabolite will be
excreted into the feces or reabsorbed into the
systemic circulation.
 The cycle in which drug is absorbed, secreted into the
bile and reabsorbed from the intestine is called
enterohepatic circulation.
 Some drugs excreted as a glucuronide conjugate
become hydrolyzed in the gut back to the parent drug
by the action of a b-glucuronidase enzyme present in
the intestinal bacteria. In this case, the parent drug
becomes available for reabsorption.

DOUBLE PEAK PHENOMENA
Some drugs like cimetidine and
ranitidine, after oral administration
produce blood concentration curve
consisting of two peaks.
The presence of double peaks has
been attributed to variability in
stomach emptying, variable
intestinal motility, presence of food,
enterohepatic cycle or failure of a
tablet dosage form.

SIGNIFICANCE OF BILIARY
EXCRETION
When a drug appears in the feces after oral administration, it is
difficult to determine whether this presence of drug is due to
biliary excretion or incomplete absorption. If the drug is given
parenterally and then observed in the feces, one can conclude
that some of the drug was excreted in the bile.
Because drug secretion into bile is an active process, this
process can be saturated with high drug concentrations.
Moreover, other drugs may compete for the same carrier
system.
With a large dose or multiple doses, a larger amount of drug is
secreted in the bile, from which drug may then be reabsorbed.
This reabsorption process may affect the absorption and

SIGNIFICANCE OF BILIARY
EXCRETION
Drugs that undergo enterohepatic circulation sometimes show a
small secondary peak in the plasma drug–concentration curve.
The first peak occurs as the drug in the GI tract is depleted; a
small secondary peak then emerges as biliary-excreted drug is
reabsorbed. This is known as double peak phenomena. Eg,
ranitidine, cimetidine
In animals, bile duct cannulation provides a means of
estimating the amount of drug excreted through the bile. In
humans, a less accurate estimation of biliary excretion may be
made from the recovery of drug excreted through the feces.
However, if the drug was given orally, some of the fecal drug
excretion could represent unabsorbed drug.

FACTORS AFFECTING
BILIARY DRUG EXCRETION
Molecular Weight of drug
Polarity of drug
Pathological condition
Route of administration

MOL. WT OF DRUGS
Drugs having mol. Wt greater than 500 are mainly excreted by
bile while drugs having mol. Wt. b/w 300-500 are excreted by
both kidney and liver and those having mol. Wt ≤ 300 are
excreted through kidney
POLARITY OF DRUG
Drugs or metabolite having high molecular weight & highly
polar groups are excreted more via this pathway
As most of drug metabolites are glucuronide conjugates & the
formation of glucuronide increases the molecular weight of
compound by 200 and above increases its polarity and thus
excretion

PATHOLOGICAL CONDITION
Pathophysiologic conditions that cause cholestasis (condition
where bile cannot flow and reach the duodenum) decrease
biliary drug excretion. e.g. half life of drug is about twice as
long in patients with biliary obstruction than patients having
no obstruction
ROUTE OF ADMINISTRATION
May also influence the amount of drug excreted into the bile
e.g. drugs given orally may be extracted by the liver into the
bile to a greater extent than if the drugs are given
intravenously

ROLE OF
TRANSPORTERS
ON HEPATIC
CLEARANCE AND
BIOAVAILABILITY
Class 1 drugs are not so much
affected by transporters because
absorption is generally good already
due to high solubility and
permeability.
Class 2 drugs are very much affected
by efflux transporters because of low
solubility and high permeability. The
limited amount of drug solubilized and
absorbed could efflux back into the GI
lumen, thus resulting in low plasma
level. Further, efflux transporter may
pump drug into bile if located in the
liver canaliculi.

ELIMINATION OF DRUG
THROUGH OTHER
ORGANS

ELIMINATION OF DRUG
THROUGH OTHER ORGANS
1. Pulmonary excretion
2. Salivary excretion
3. Mammary excretion
4. Skin excretion
5. Genital excretion

1. PULMONARY EXCRETION
 Organ involved= Lungs
 Lungs contains various drug metabolizing enzymes
 Appropriate route for gaseous and volatile substances due to its
anatomical position in circulatory system, large alveolar area and
high blood flow.
 E.g. alcohol, and many gaseous anesthetics
 The breathalyzer test based on quantitative pulmonary excretion of
ethanol.

2. SALIVARY EXCRETION
 Saliva volume is 1-2 liters per day with flow rates ranging from 0.5 ml/min.
 Saliva pH ranges from 6.2 - 7.4.
 It also contains a number of enzymes including amylase, ptylin, lipase and
esterases.
 The excretion of drugs in saliva is determined largely by pH-partition
properties
 Examples of drugs excreted in saliva are:
sulfonamides, phenobarbital, rifampicin, phenytoin, theophylline, salicylates, acetaminophen,
digoxin etc.
 In many cases salivary concentration represents the free drug concentration in
plasma. Can act as a mean of monitoring plasma concentration if the partition
coefficients between plasma and saliva remain constant e.g. rifampicin
 The bitter after taste in the mouth of a patient on medication is an indication
of drug excretion in saliva. May also result in localized side effects e.g. black
hairy tongue (antibiotics), gingival hyperplasia (phenytoin)

2. SALIVARY EXCRETION
Transport of drugs from blood to saliva depends on
 Lipid solubility of drug
 pH of saliva
 pKa of drug
 Plasma protein binding
Secretion of drugs in saliva is usually passive process but active transport
may be involved.
 Drugs which are excreted in saliva can undergo recycling similar to
biliary cycling e.g. sulfonamides and clonidine -Salivary recycling

3. MAMMARY EXCRETION
 Excretion of drugs in milk is a passive process and is dependent
upon pH partition behavior, molecular weight, lipid solubility and
degree of ionization.
 pH of milk ranges from 6.4 - 7.6
 Free, unionized, lipid soluble drugs diffuse into the mammary cells
passively.
 The extent of drug excretion in milk can be determined from
milk/plasma drug concentration ratio (M/P).
 Since milk is acidic comparison to plasma, as in the case of saliva,
weakly basic drugs concentrate more in milk and have M/P ratio
greater than 1. The opposite is true for weakly acidic drugs.

3. MAMMARY EXCRETION
The amount of drug excreted in milk is generally less than 1%. The
infant’s immature renal and hepatic function can delay excretion or
metabolic inactivation of drugs. This could lead to accumulation in
infant’s blood. Some potent drugs such as barbiturates and morphine
may induce toxicity in infants.
Discoloration of teeth with tetracycline and jaundice due to
interaction of bilirubin with sulfonamides are examples of adverse
effects precipitated due to drug excretion in the milk. Nicotine is also
secreted in the milk of mothers who smoke.
Thus, wherever possible, nursing mothers should avoid drugs and
smoking and if medication is unavoidable, the infant should be bottle
fed.

4. SKIN EXCRETION
 Some drugs are excreted through skin but it is of little importance
 Arsenic and mercury are excreted in small quantities through the
skin in sweat.
 Sweat is found at moderately acidic to neutral pH levels,
typically between 4.5 and 7.0.
Drugs excreted through the skin via sweat also follow pH-partition
hypothesis.
Passive excretion of drugs and their metabolites through skin is
responsible to some extent for the urticaria and dermatitis and other
hypersensitivity reactions.
Compounds such as benzoic acid, salicylic acid, alcohol and heavy
metals like lead, mercury and arsenic are excreted in sweat.
Disadvantage of this route include difficulty in collecting sweat

5. GENITAL EXCRETION
Reproductive tract and genital secretions may contain the excreted drugs.
Some drugs have been detected in semen eg. antiretroviral drugs like
lamivudine

EXCRETION PATHWAYS, TRANSPORT
MECHANISMS & DRUG EXCRETED
Excretory
route
Mechanism Drug Excreted
Urine GF/ ATS/ ATR, PTR Free, hydrophilic, unchanged drugs/
metabolites of MW< 300
Bile Active secretion Hydrophilic, unchanged drugs/
metabolites/ conjugates of MW >500
Lung Passive diffusion Gaseous &volatile, blood & tissue
insoluble drugs
saliva Passive diffusion
Active transport
Free, unionized, lipophilic drugs. Some
polar drugs
Milk Passive diffusion Free, unionized, lipophilic drugs (basic)
Sweat/ Passive diffusion Free, unionized lipophilic drugs

REFERENCES:
- Applied Pharmacokinetics by LEON
SHARGEL, 7th edition, pg 309-350
-BIOPHARMACEUTICS by Milo Gibaldi
- Kulkarni
-Biopharmaceutics by Gul majid khan

• Drugs that are competitive inhibitors of each other for drug
protein binding may affect clearance of each other.
• Drugs which influence the hepatocytes function, effect the
extraction ratio and hence the hepatic clearance.
• Similarly, in case of hepatic diseases, the blood flow to the
liver and its metabolizing activity is altered, which ultimately
influence the hepatic clearance.

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