Pharmacokinetics

Pharmacokinetics
Course Title: Pharmacology I
Course No.: PHAR 2113
Prepared by: Biswajit Biswas
Reference: Goodman & Gilman’s Manual of Pharmacology and Therapeutics

Pharmacokinetics
1. Refers to
i) movement of drug in the body and
ii) alteration of drug by the body.
It includes absorption, distribution, biotransformation, and excretion (ADME) of drug from
the body.
2. Quantitative study of drug movements in, through and out of body.
3. It determines
i. Rout of drug administration
ii. Dose
iii. Onset of action
iv. Duration of action
v. Cmax
vi. Tmax

Biological Membrane
• Lipid bilayer
• 100 A0 thick
• Having hydrophilic (polar head) and
hydrophobic (non-polar tail ) end.
Polar group - glycerol phosphate + ethanol amine /
choline or hydroxyl group of cholesterol -
projected out side of the surface.
Hydrocarbon chain embedded
in the matrix.

Absorption
Site of administration → Systemic circulation.
Factors influence drug absorption:
a. Aqueous solubility of drug
Solid drug  dissolution  absorbed
Higher the water solubility  higher the rate of absorption
Thus solution absorb faster rate then solid drugs.
b. Concentration.
c. Area of absorbing surface
d. Vascularity of the absorbing surface
e. Route of drug administration.

Mechanism of Absorption
Drugs are absorbed through the membrane either by
a. Passive diffusion and filtration or
b. Specialized transport
Passive diffusion:
 Movement of drugs through membrane towards concentration gradient.
 Lipid soluble drugs are diffused by dissolving in the lipoidal matrix of the membrane.
 Such transfer is directly proportional to the magnitude of the concentration gradient across
the membrane, to the lipid–water partition coefficient of the drug, and to the membrane
surface area exposed to the drug.
 After a steady state is attained, the concentration of the unbound drug is the same on both
sides of the membrane if the drug is a nonelectrolyte.
 For ionic compounds, the steady-state concentrations depend on the electrochemical gradient
for the ion and on differences in pH across the membrane.

Drug absorption are influenced by pH:
Most of the drugs are weak electrolyte (weak acids or bases) and their ionization is pH dependent.
However, strong electrolyte completely dissociates. The ionization of weak electrolyte are given by
the equation:
pH = pKa + log
This equation relates the pH of the medium around the drug and the drug’s acid dissociation
constant (pKa) to the ratio of the protonated (HA or BH+) and unprotonated (A– or B) forms, where
HA→ A– + H+ (Ka = [A–][H+]/[HA]) describes the dissociation of an acid, and BH+ → B + H+,
( Ka = [B][H+]/[BH+]) describes the dissociation of the pronated form of a base.
At steady state, an acidic drug will accumulate on the more basic side of the membrane and a basic
drug on the more acidic side—a phenomenon termed ion trapping.
[Protonated form]
[Unprotonated form]

 Thus weak acidic drug which is formed salt with strong cation are ionized at alkaline pH of
intestine and weak basic drugs are ionized at acidic pH of the stomach.
 Acidic drug e.g. Aspirin remain unionized at acidic PH of stomach and absorbed from the
stomach area; while bases are largely absorbed from intestine.
 Acidic drug which absorbed from the stomach to the gastric mucosal cell, revert to ionized
form within the cell (PH= 7 ) and only slowly passes to the extra cellular fluids
 Basic drug is attained in high concentration intracellularly from intestine.

Filtration:
 Passage of drugs through aqueous pore in the membrane or through para cellular spaces. This
process can be accelerated if the hydrodynamic flow of solvent occur under osmotic pressure
gradients.
 Lipid insoluble drugs cross through membrane by filtration if their molecular size is smaller
than the diameter of the pores.
 Majority of the cell have very small pore size (4 A0) and drug with MW more than 100 –200, can
not penetrate through this pore. However, the capillaries of blood vessels ( except blood brain
barrier) have lager in (40 A0) size and most of the drug even albumin can diffuse through this
capillaries. The diffusion of drugs solely depend on the rate of blood flow.

Special transport:
1. Carrier mediated 2. Pinocytosis
1. Carrier mediated:
Drug + Carrier = Drug-Carrier complex; then translocates.
Polar molecules (Hydrophilic) coated with hydrophobic layer thus facilitate transport.
Carrier transport is specific, saturable and competitively inhibited by the analogues which use the
same carrier.
2 types--
i) Active transport
ii) Facilitate diffusion.

i) Active transport:
 Against concentration gradation
 Need energy and can be blocked by metabolic poisons
 Selective accumulation occur
 Natural metabolites are actively absorbed.
Primary Active Transport: Membrane transport that directly couples with ATP hydrolysis is called
primary active transport.
Secondary Active Transport: In secondary active transport, the transport across the plasma membrane
of one solute against its concentration gradient is driven energetically by the transport of another
solute in accordance with its concentration gradient.

ii) Facilitate diffusion:
 More rapid than simple diffusion, translocates even non-diffusible substrate but along the
concentration gradation.
 Membrane transporters may facilitate diffusion of ions and organic compounds across the plasma
membrane; this facilitated diffusion does not require energy input.
 Just as in passive diffusion, the transport of ionized and non-ionized compounds across the plasm
a membrane occurs down their electrochemical potential gradient.
2. Pinocytosis:
 Process of transport of drug across the cells in particulate form
by forming vesicles.
 Bigger molecules like protein are transported by this process.

Effect of route of administration on
drug absorption
 Oral route
 Subcutaneous route or intramuscular route
 Topical route
Oral Route:
a) Effective barrier:
Epithelial lining (unionized lipid soluble drug- alcohol); rate of absorption is proportional to their
lipid : water partition co-efficient.
Acidic drug like aspirin, salicylates, barbiturate---- absorbed well from stomach,
Basic drug like morphine, atropine, quinine etc. absorb well form duodenum.

drug absorption
b) Even acidic drug absorption from stomach is less due to -
 Thick mucus membrane
 Small surface area
 Slow dissolution
c) Presence of food:
 Interfere absorption by
 Dilution of drugs
 Delay emptying
 Drug-food interaction
d) Certain drugs degrade by the acidic environment of stomach e.g. Pen-G, Insulin, Cephalosporin etc.
Enteric coating or surface coating or other sustained release product free from such draw back.

drug absorption
e) Absorption also effected by drug-drug interaction.
Formation of complex -
Phenytion with sucralfate
Alkaloid with tannin containing preparation.
Can minimized by providing suitable gap between two drugs administration.
f) Effected by alteration of intestinal microbial flora
Enterohepatic circulation of oral contraceptives and digoxin.
g) Drugs also can alter GUT wall motility
e.g. Anticholinergic, tricyclic antidepressent, morphine, metaclopramid - relaxes gut wall.
Neomycin, Vinblastine, Methotraxate - damage the mucus membrane.

drug absorption
Subcutaneous:
Drug deposited directly into the vicinity of the capillaries. Lipid soluble drug directly passes across
the whole surface of the capillary membrane.
Capillaries are highly porous- do not obstruct ionized molecules, even large molecules are absorbed
through lymphatic system.
Drug those can not absorbed through oral route can absorbed through IM or SC
 SC absorption is slower then IM
 But both are faster than oral route.
 Massage or application of heat accelerate the absorption
 Addition of Vasoconstrictor- adrenaline retard absorption.

drug absorption
Topical site:
 Depending on the lipid solubility of the drugs.
 Only few drugs can penetrate through the intact skin, e.g. nitroglycerin, hyoscine, estradiol.
 Corticosteroid- applied over skin can have systemic effect and pituitary adrenal suppression.
 Absorption can be promoted by rubbing the skin, also incorporation of smoothening agent or
vasodilating agent enhance absorption.
 Abrasive surface – accelerate the absorption process.

Bioavailability
Measured fraction of administrated dose of drug available into the systemic circulation in unchanged
form.
It refers to the rate and extent of absorption from a dosage form and determined by the concentration-
time curve.
Variation in bioavailability:
Reasons:
1. Route of administration: Bioavailability is 100% from i.v. route but frequently lower after oral
ingestion due to either incomplete absorption or fast pass metabolism. Incomplete absorption may
occur from S.C injection due to local tissue binding but usually less common.

Bioavailability
2.Variation in formulation:
Oral formulation of drug from different manufacturer or the same manufacturer of different batches
of chemically equivalent drug may not be biologically equivalent.
Biological equivalent: When two preparation of same drug are considered and the rate and extent of
absorption do not vary significantly at the given test condition, then those two drugs are considered to
be biologically equivalent.
3. Bioavailability depend on the rate and extent of disintegration and dissolution.
Before drug to be absorbed from oral dosages form they require to disintegrate, i.e. individual particle
must be detached from each other, and then dissolute and absorb.
Disintegration depends on type of additive materials used during preparation & force of compaction.
Dissolution depend on : i) Drug solubility ii)Particle size iii) Their crystal form and physical properties

Bioavailability
PlasmaConcentration(mg/ml)
Time (h)
AUC p.o.
F = ------------ x 100%
AUC i.v.
AUC –> Area Under The Curve
F –> Bioavailability
Difference in bioavailability seen with poorly soluble drugs. Reduction of particle size will enhance
drug solubility by increasing the surface area increase bioavailability  reduces the dose size.
For e.g. the dosage of Griseofluvin and Spironolactone can be reduced to its half of the quantity
while given in micro fine powder form.

Distribution of Drugs
Once the drugs gain into the blood stream, it translocates to the other part where initially had no drugs
(movement according to concentration gradient).
Factor governing the distribution of drugs:
i. Lipid : water partition co-efficient of drug (lipid insoluble drug do not enter cell , so Vd is less)
ii. pKa value of drug (high pKa at physiological condition reduce the Vd)
iii. Degree of plasma protein bindings (reduce Vd)
iv. Affinity for different tissue (increase Vd)
v. Fat : lean body mass ratio (if ratio more Vd is less incase of electrolyte)
vi. Disease like CHF, uremia, cirrhosis (reduce Vd)
V = Volume of Distribution.

Volume of Distribution
Definition: Apparent Volume of distribution is defined as the volume that would accommodate all the
drugs in the body, if the concentration was the same as in plasma. Expressed in liters (L).
Vd =
Ex: Chloroquin – 13000 liters, Digoxin – 420 L, Morphine – 250 L and Propranolol – 280 L, Streptomycin
and Gentamicin – 18 L.
Why it is called apparent volume of distribution?
`Vd` is an imaginary Volume of Fluid which will accommodate the entire quantity of the drug in the
body, if the concentration throughout this imaginary volume were same as that in plasma.
Dose administered IV
Plasma concentration

Redistribution
Highly lipid soluble drug given I.V. or inhalation, initially rapidly get distributed to the organ
system with high blood flow e.g. brain, kidney, liver, heart etc. and then to the organ of less blood
flow or more bulky tissue e.g. muscles, fat, adipose tissue. Thus plasma concentration of drugs
gradually falls and slowly withdraw from high blood flow organ to bulky tissue.
Greater the lipid solubility of drug higher the rate of redistribution.
Brain and CSF Penetration
Blood brain barrier (BBB): Capillary endothelial cells of brain have tight junction and lack the entry
of larger molecules due to small intracellular pores. Further, an investment of neural covering (Glial
foot), gives the capillary more impermeable to large drugs. This capillary junction together with glial
foot constitute the so called blood brain barrier.

Brain and CSF Penetration
 BBB is lipoidal and limits the entry of non-lipid soluble drugs (amikacin, gentamicin,
neostigmine etc.). Only lipid soluble unionized drugs penetrate and have action on the CNS.
 Efflux carriers like P-gp (glycoprotein) present in brain capillary endothelial cell (also in intestinal
mucosal, renal tubular, hepatic canicular, placental and testicular cells) extrude drugs that enter
brain by other processes.
 Inflammation of meninges of brain increases permeability of BBB.
 Drug modification is required to target the brain. Dopamine (DA) does not enter brain, but its
precursor levodopa does. This is used latter in parkinsonism. (Reff: Goodman & Gilman’s Manual
of Pharmacology and Therapeutics – Treatment of CNS Degenerative Disorder).

Placental Transfer
 Lipoidal in nature, thus allow free passage of lipophilic drugs and restrict only hydrophilic
drugs.
 Placental P - glycoprotein serves to limit foetal exposure to maternally administrated drugs.
 However, long time existence of non-lipid soluble drug at higher concentration in the maternal
circulation, restricted amount can penetrate into the placenta , and can cause harm to fetus.
 Thus, it is incomplete barrier and almost any drug can cross and effect the fetus.
Plasma Protein Binding (PPB)
 Most drugs possess physicochemical affinity for plasma proteins.
 Acidic drugs bind to plasma albumin and basic drugs to α1-glycoprotein
 Extent of binding depends on the individual compound.
 Increasing concentration of drug can progressively saturate the binding sites

Plasma Protein Binding (PPB)
The clinical significance of PPB:
 Highly PPB drugs are largely restricted to the vascular compartment and tend to have lower Vd.
 The PPB fraction is not available for action.
 There is an equilibration between PPB fraction of drug and free molecules of drug.
 The drugs with high physicochemical affinity for plasma proteins (e.g. aspirin, sulfonamides,
chloramphenicol) can replace the other drugs (e.g. acenocoumarol, warfarin) or endogenous
compounds (bilirubin) with lower affinity.
 High degree of protein binding makes the drug long acting, because bound fraction is not
available for metabolism, unless it is actively excreted by liver or kidney tubules.
 Generally expressed plasma concentrations of the drug refer to bound as well as free drug.
 In hypoalbuminemia, binding may be reduced and high concentration of free drug may be
attained (e.g. phenytoin).

Tissue Storage
 Drug may accumulate in specific tissue or organs.
 Drug tend to store different tissue contribute to long duration of action and larger V.
 May cause local toxicity.
i. Heart and skeletal muscles – digoxin (to muscle proteins)
ii. Liver – chloroquine, tetracyclines, digoxin
iii. Kidney – digoxin, chloroquine
iv. Thyroid gland – iodine
v. Brain – chlorpromazine, isoniazid, acetazolamide
vi. Retina – chloroquine (to nucleoproteins)
vii. Iris – ephedrine, atropine (to melanin)
viii. Bones and teeth – tetracyclines, heavy metals (to mucopolysaccharide of connective tissue)
ix. Adipose tissues – thiopental, ether, minocycline, DDT.

Biotransformation
Metabolism of Drugs
What is Biotransformation?
 Chemical alteration of the drug in the body
 Aim: to convert non-polar lipid soluble compounds to polar lipid insoluble compounds
to avoid reabsorption in renal tubules
 Most hydrophilic drugs are less biotransformed and excreted unchanged –
streptomycin, neostigmine and pancuronium etc.
 Biotransformation is required for protection of body from toxic metabolites
 Primary site of biotransformation are kidney, liver , intestine, lung and plasma.

Results of Biotransformation
1. Active drug and its metabolite to inactive metabolites – most drugs
(ibuprofen, paracetamol, chlormphenicol etc.)
2. Active drug to active product
(phenacetin – acetminophen or paracetamol,
morphine to Morphine-6-glucoronide,
digitoxin to digoxin etc.)
3. Inactive drug to active/enhanced activity (prodrug) –
levodopa - carbidopa,
prednisone – prednisolone
enlpril – enlprilat)
4. No toxic or less toxic drug to toxic metabolites (Isonizide to Acetyl isoniazide)

Biotransformation
2 (two) Phases of Biotransformation:
Phase I or Non-synthetic – metabolite may be
active or inactive
Phase II or Synthetic – metabolites are
inactive (Morphine – M-6 glucouronide is
exception)

Phase I - Oxidation
Most important drug metabolizing reaction – addition of oxygen or (– ve) charged
radical or removal of hydrogen or (+ ve) charged radical
Various oxidation reactions are – oxygenation or hydroxylation of C-, N- or S-atoms;
N or o – dealkylation
Involve – cytochrome P-450 monooxygenases (CYP), NADPH and Oxygen
More than 100 cytochrome P-450 isoenzymes are identified
In human - only 3 isoenzyme families important – CYP1, CYP2 and CYP3
Examples – Barbiturates, phenothiazines, paracetamol and steroids

Phase I - Reduction
This reaction is conversed of oxidation and involves CYP 450 enzymes working in the
opposite direction.
Examples - Chloramphenicol, levodopa, halothane and warfarin
Phase I - Hydrolysis
This is cleavage of drug molecule by taking up of a molecule of water. Similarly
amides and polypeptides are hydrolyzed by amidase and peptidases. Hydrolysis
occurs in liver, intestines, plasma and other tissues.
Examples - Choline esters, procaine, lidocaine, pethidine, oxytocin
Cyclization (formation of ring structure) Decyclization (opening up of ring structure)

Phase II Metabolism
Glucuronide conjugation: Compounds with hydroxyl or carboxylic acid group are
easily conjugated with glucuronic acid - derived from glucose
Examples: Chloramphenicol, aspirin, morphine, metronidazole, bilirubin, thyroxine.
Acetylation: Compounds having amino or hydrazine residues are conjugated with the
help of acetyl CoA, e. g. sulfonamides, isoniazid.
Sulfate conjugation: The phenolic compounds and steroids are sulfated by
sulfokinases, e.g. chloramphenicol, adrenal and other steroids.
Methylation: The amines and phenols can be methylated. Methionine and cysteine act
as methyl donors. Examples: adrenaline, histamine, nicotinic acid.
Ribonucleoside/nucleotide synthesis: Activation of many purine and pyrimidine
antimetabolites used in cancer chemotherapy

Drug Metabolizing Enzymes
Micrisomal enzymes:
Located into the smooth
endoplasmic reticulam
(microtubules) of liver, lung,
kidney, intestinal mucosa
Ex- monooxygenase, cyt-
P450, glucuronyl transferase.
They carry out most of the
oxidation, reduction,
hydrolysis and glucuronide
conjugation.
Non- microsomal enzymes:
They present in the cytoplasm ,
mitochondria especially in
hepatic cell and other tissue ,
even in plasma.
Ex. Flavoprotein oxidases,
esterases
Reaction catalyze by them are
some oxidation, many
hydrolytic reaction and all most
all conjugation reaction

Excretion
Out passage of systemically absorbed drug through excretion organ or secretion organ.
Routes of drug excretion
Urine:
Most important channel of excretion for most of the drug. Excrete through kidney
Faeces:
Unabsorbed fraction are excreted.
Drug is absorbed  glucuronidated or sulfatated in the liver and secreted through the
bile  glucuronic acid/sulfate is cleaved off by bacteria in GI tract  drug is reabsorbed
(steroid hormones, rifampicin, amoxycillin, contraceptives)and excreted through urine.
Anthraquinone, heavy metals  directly excreted in colon.

Routes of drug excretion
Exhale air:
Gases and volatile liquid- eliminate through lung, irrespective of their lipid solubility.
Ex- general anesthetics, paraldehyde, alcohol etc.
Exhale air:
Gases and volatile liquid- eliminate through lung , irrespective of their lipid solubility.
Ex- general anesthetics, paraldehyde, alcohol etc.
Milk:
Most of the lipid soluble and less protein bound drugs cross better into the breast milk.
Milk has lower pH (7) than plasma thus basic drug concentrated more in it. However the
total amount of drug excrete through breast milk is very minute quantity, thus causing
without any ill effect to the suckling infant.

Renal Excretion
Glomerular Filtration:
 Normal GFR – 120 ml/min
 Glomerular capillaries have pores larger than usual
 The kidney is responsible for excreting all water soluble substances
 All non-protein bound drugs (lipid soluble or insoluble) presented to the glomerulus are
filtered
 Glomerular filtration of drugs depends on their plasma protein binding and renal blood
flow - Protein bound drugs are not filtered !

Renal Excretion
Tubular Reabsorption:
1. Depend on a) lipid solubility b) ionization of drug at urinary pH.
a) Lipid soluble drug - filtered at Glomerulus and 99% diffuse back into the tubules.
b) Lipid insoluble drugs can not be reabsorbed. Ex- Amino glycosides, Quaternary
ammonium compound etc.
2. Change in urinary pH effects tubular reabsorption
a) Weak base ionize more in acidic media and less reabsorbed.
b) Weak acid more ionize in alkaline media and are less reabsorbed

Renal Excretion
Tubular Secretion:
Energy dependent active transport of drug through the renal tubule – reduces the free
concentration of drugs – further, more drug dissociation from plasma binding – again more
secretion.
– organic acid transport
– organic base transport.

Renal Excretion
Glomerulus
Efferent
arteriole
Plasma
protein
Blood
vessel
Tubular
cell
Tubular
lumen
BD
BD
FD
BD
BD FD BD FDx
DX
DX
UD
ID
1%
99%
Urine pH

Kinetics of Elimination
Pharmacokinetics - F, V and CL
Clearance: The clearance (CL) of a drug is the theoretical volume of plasma from which
drug is completely removed in unit time.
CL = Rate of elimination (RoE)/C
Example = If a drug has 20 mcg/ml conc. and Rate of Elimination is 100 mcg/min
CL = 100/20 = 5 ml /min.
First Order Kinetics (exponential): Rate of elimination is directly proportional to drug
concentration, CL remaining constant.
Constant fraction of drug is eliminated per unit time.
Zero Order kinetics (linear): The rate of elimination remains constant irrespective of drug
concentration
CL decreases with increase in concentration.

Pharmacokinetics - F, V and CL
Plasma half-life:
Defined as time taken for its plasma concentration to be reduced to half of its original value.
T 1/2 = In 2 / k
In 2 = 0.693
k = elimination rate constant = CL / V
T 1/2 = 0.693 x V / CL
1 half-life …………. 50%
2 half-lives………… 25%
3 half-lives …….…..12.5%
4 half-lives ………… 6.25%
50 + 25 + 12.5 + 6.25 + 3.125 = 97% drug is eliminated after 5 Half Lives.
CL = RoE/C
V = dose IV/C

Loading Dose:
A single or few repeated or series of doses that may be given at the very beginning of the
therapy to reach the desire plasma concentration rapidly.
LD= Target Cp x V / Fraction of dose(F)
Thus, loading dose govern by V and fraction of dose. Plasma clearance (CL) or plasma half
life do not have any influence on Loading dose.
Maintenance Dose:
It is the amount of drug require to give in each intervals to replace the drug eliminated at
that particular interval since the preceding dose require to maintain a steady state of drug
always in the body.
Maintenance dose = dosing rate x dosing interval
Dosing rate = Target Cp x CL.

Pharmacokinetics

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