metabolism and elemination

1. PRESENTED BY :
DR. MAMTA
ASST. PROFESSOR
(MMCP)

2. CONTENTS
 METABOLISM(biotransformation reactions)
 Microsomal & Non-Microsomal Enzymes
 EXCRETION OF DRUGS
 KINETICS OF ELEMINATION
2

3. METABOLISM (Biotransformation)
 Biotransformation means chemical alteration of the
drug in the body.
 It is needed to render nonpolar (lipid-soluble)
compounds polar (lipid insoluble) so that they are not
reabsorbed and are excreted easily.
 Most hydrophilic drugs, e.g. streptomycin,
neostigmine, pancuronium, etc. are little
biotransformed and are largely excreted unchanged.
 The primary site for drug metabolism is liver; others
are—kidney, intestine, lungs and plasma.
3

4. 4

5. Biotransformation of drugs may
lead to the following:
I. Inactivation :Most drugs and their
active metabolites are rendered
inactive or less active metabolites
(e.g. ibuprofen, paracetamol,
lidocaine, chloramphenicol,
propranolol).
II. Active metabolite from an active
drug: Many drugs have been found
to be partially converted to one or
more active metabolite; (e.g.
phenacetin – acetaminophen).
III. Activation of inactive drug: Few
drugs are inactive as such and need
conversion in the body to one or
more active metabolites. Such a drug
is called a Prodrug (e.g. levodopa –
carbidopa).
5

6. Biotransformation - classification
I. Nonsynthetic/Phase I/Functionalization reactions-metabolite may be
active or inactive
II. Synthetic/Conjugation/ Phase II reactions-metabolites are inactive
 Phase 1 – Oxidation
Most important drug metabolising reaction – addition of oxygen or removal
of hydrogen. In many cases the initial insertion of oxygen atom into the drug
molecule produces short lived highly reactive intermediate which then convert
to more stable compounds.
• Examples – Barbiturates, phenothiazines, paracetamol and steroids
• Oxidative reactions are mostly carried out by a group of monooxygenases in the
liver, which in the final step involve a cytochrome P-450 haemoprotein,
NADPH, cytochrome P- 450 reductase and molecular O2.
 Nonmicrosomal Enzymatic Oxidation: Some drugs are oxidized by non-
microsomal enzymes (mitochondrial and cytoplasmic)
• Alcohol – Dehydrogenase
• Adrenaline – MAO and COMT
• Mercaptopurine – Xanthine oxidase
6

7. Phase 1 - Reduction
This reaction is converse of oxidation and involves CYP450
enzymes working in the opposite direction. Alcohols,
aldehydes, are reduced. Drugs primarily reduced are
chloralhydrate, chloramphenicol, halothane, warfarin.
Phase 1 -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.
E.g. – acetylcholine is hydrolysed by ‘cholinestrase’ and
converted into choline and acetic acid.
7

8. Phase-I Cyclization: This is formation of ring structure
from a straight chain compound, e.g. proguanil.
Phase-I Decyclization: This is opening up of ring
structure of the cyclic drug molecule, e.g. barbiturates,
phenytoin. This is generally a minor pathway.
8

9. Phase-II synthetic reactions
These involve conjugation of the drug or its phase I metabolite with
an endogenous substrate, usually derived from carbohydrate or
amino acid, to form a polar highly ionized organic acid, which is
easily excreted in urine or bile.
I. Glucoronide Conjugation – most important synthetic reaction
 Compounds with hydroxyl or carboxylic acid group are easily
conjugated with glucoronic acid- derived from glucose.
 This reaction is carriedout by a group of UDP-glucuronosyl
transferases (UGTs).
 Examples – chloramphenicol, aspirin, morphine,
metronidazole, bilirubin, thyroxine
II . Acetylation – Compounds having amino or hydrazine residues
are conjugated with the help of acetyl coenzyme-A. , e.g.
sulfonamides, isoniazid.
9

10. III. Methylation - The amines and phenols can be methylated by
methyl transferases (MT); methionine and cysteine acting as
methyl donors, e.g. adrenaline, histamine, nicotinic acid
IV. Sulfate conjugation - The phenolic com- pounds and
steroids are sulfated by sulfotrans- ferases (SULTs), e.g.
chloramphenicol, methyldopa, adrenal and sex steroids.
V. Glycine conjugation: Salicylates, nicotinic acid and other
drugs having carboxylic acid group are conjugated with
glycine, but this is not a major pathway of metabolism.
VI. Glutathione conjugation This is carried out by glutathione-
S-transferase (GST). However, it serves to inactivate
highly reactive intermediates formed during metabolism
of certain drugs, e.g. paracetamol.
VII. Ribonucleoside/nucleotide synthesis: This pathway is
important for the activation of many purine and pyrimidine
antimetabolites used in cancer chemotherapy.
10

11. MICROSOMAL ENZYME
These are located on smooth endoplasmic reticulum (a
system of microtubules inside the cell), primarily in
liver, also in kidney, intestinal mucosa and lungs.
The monooxygenases, cytochrome-P450, UGTs,
epoxide hydrolases, etc. are microsomal enzymes.
They catalyse most of the oxidations, reductions,
hydrolysis and glucuronide conjugation.
Microsomal enzymes are inducible by drugs, diet and
other agencies.
11

12. NON-MICROSOMAL ENZYMES
Present in the cytoplasm and mitochondria of hepatic
cells as well as in other tissues including plasma.
The esterases, amidases, some flavoprotein oxidases
and most conjugases are nonmicrosomal.
Reactions catalysed are: Some oxidations and
reductions, many hydrolytic reactions and all
conjugations (except glucuronidation)
The nonmicrosomal enzymes are not inducible but
many show genetic polymorphism
***Both microsomal and nonmicrosomal enzymes are
deficient in the newborn, especially premature,
making them more susceptible to many drugs.
12

13. Hofmann elimination
 This refers to inactivation of the drug in the body
fluids by spontaneous molecular rearrangement
without the agency of any enzyme, e.g. atracurium.
13

14. Inhibition of enzymes
 One drug can competitively inhibit the metabolism of another if it
utilizes the same enzyme or cofactors.
 A drug may inhibit one isoenzyme while being itself a substrate of
another isoenzyme, e.g. quinidine is metabolized mainly by CYP3A4
but inhibits CYP2D6.
 Inhibition of drug metabolism occurs in a dose related manner and can
precipitate toxicity of the object drug
14

15. Induction of enzyme
 Many drugs, insecticides and carcinogens interact with
DNA and increase the synthesis of microsomal
enzyme protein, especially cytochrome P-450 and
UGTs As a result rate of metabolism of inducing drug
itself and/or other drugs is increased.
Possible uses of enzyme induction
1. Cushing’s syndrome: phenytoin may reduce the
manifestations by enhancing degradation of adrenal
steroids which are produced in excess.
2. Chronic poisonings: by faster metabolism of the
accumulated poisonous substance.
3. Liver disease.
15

16. FIRST PASS (PRESYSTEMIC)
METABOLISM
A drug given via the oral route may be extensively
metabolized by the liver before reaching the systemic
circulation (high first-pass effect).
•The same drug—given IV—bypasses the liver,
preventing the first-pass effect from taking place, and
more drug reaches the circulation.
16

17. Excretion
Excretion is the passage out of systemically absorbed drug.
Drugs and their metabolites are excreted in:
I. Urine: Through the kidney. It is the most important channel
of excretion for majority of drugs.
RENAL EXCRETION : The kidney is responsible for excreting
all water soluble substances.
 Glomerular filtration: Glomerular capillaries have pores
larger than usual; all nonprotein bound drug (whether lipid-
soluble or insoluble) presented to the glomerulus is filtered.
Glomerular filtration rate (g.f.r.), normally ~ 120 ml/min
17
Net renal excretion = (Glomerular filtration + tubular secretion) – tubular
reabsorption

18. 2. Tubular reabsorption: This occurs by passive diffusion and depends
on lipid solubility and ionization of the drug at the existing urinary pH.
Lipid-soluble drugs filtered at the glomerulus back diffuse in the
tubules because 99% of glomerular filtrate is reabsorbed, but nonlipid-
soluble and highly ionized drugs are unable to do so.
Changes in urinary pH affect tubular reabsorption of drugs that are
partially ionized—
• Weak bases ionize more and are less reabsorbed in acidic urine.
• Weak acids ionize more and are less reabsorbed in alkaline urine.
3. Tubular secretion: This is the active transfer of organic acids and
bases by two separate classes of relatively nonspecific transporters
(OAT “For acids”and OCT “for bases”) which operate in the proximal
tubules. Active transport of the drug across tubules reduces
concentration of its free form and promotes dissociation of protein
bound drug, which then becomes available for secretion
 Thus, protein binding, which is a hinderance for glomerular
filtration of the drug, is not so (may even be facilitatory) to
excretion by tubular secretion.
18

19.  II. FAECES: Apart from the unabsorbed fraction, most of the drug
present in faeces is derived from bile. Liver actively transports into bile
organic acids (especially drug glucuronides by OATP) organic bases (by
OCT), other lipophilic drugs (by P-gp) and steroids by distinct nonspecific
active transport mechanisms. Relatively larger molecules (MW > 300) are
preferentially eliminated in the bile. Most of the free drug in the gut,
including that released by deconjugation of glucuronides by enteric bacteria
is reabsorbed (enterohepatic cycling) and ultimate excretion occurs in urine
(Fig). Only the remaining is excreted in the faeces. Enterohepatic cycling
contributes to longer stay of the drug in the body. Drugs that attain high
concentrations in bile are erythromycin, ampicillin, rifampin, tetracycline,
oral contraceptives, vecuronium, phenolphthalein.
 III. Exhaled air: Gases and volatile liquids(general anaesthetics, alcohol)
are eliminated by lungs, irrespective of their lipid solubility. Lungs also serve
to trap and extrude any particulate matter that enters circulation.
19

20. 20

21. 4. Saliva and sweat: These are of minor importance for drug excretion.
Lithium, pot. iodide, rifampin and heavy metals are present in these
secretions in significant amounts. Most of the saliva along with the
drug in it, is swallowed and meets the same fate as orally taken drug.
 5. Milk: The excretion of drug in milk is not important for the mother,
but the suckling infant. Most drugs enter breast milk by passive
diffusion.
21

22. KINETICS OF ELIMINATION
Drug elimination is the sumtotal of metabolic inactivation and
excretion.
 Clearance (CL): The clearance of a drug is the theoretical
volume of plasma from which the drug is completely
removed in unit time It can be calculated as
CL = Rate of elimination/C
:where C is the plasma concentration.
 For majority of drugs follows:
 First order kinetics: The rate of elimination is directly
proportional to the drug concentration, CL remains constant;
or a constant fraction of the drug present in the body is
eliminated in unit time.
22

23. Few drugs follows:
 Zero order kinetics: The rate of elimination remains
constant irrespective of drug concentration, CL decreases
with increase in concentration; or a constant amount of the
drug is eliminated in unit time, e.g. ethyl alcohol. This is
also called capacity limited elimination or Michaelis-
Menten elimination.
23

24. 24
ELIMINATION OF DRUG
[ T ½ ]

25. ELIMINATION OF DRUG
(HOW LOG DRUG STAYS IN BODY)
FIRST WE NEED TO RECALL THAT –
ELIMINATION KINETICS of drugs can be of
2 Types
FIRST ORDER (EXPONENTIAL)or
ZERO ORDER (LINEAR)
25

26. Plasma half-life
The Plasma half-life (t½) of a drug is the time taken for its
plasma concentration to be reduced to half of its original value.
Taking the simplest case of a drug which has rapid one
compartment distribution and first order elimination, and is
given i.v. a semilog plasma concentration-time plot as shown in
Fig. 3.5 is obtained.
The plot has two slopes:
• initial rapidly declining (α) phase—due to distribution.
• later less declined (β) phase— due to elimination.
26

27. IV Drug
Distribution
[α] Phase
Elimination
[β] Phase
0 4 8 12 16 20 24 28 32 36
TIME (HOURS)
LOG-PLASMA CONCENTRATION vs. TIME PLOT
16
2
8
4
1
64
32

28. ELIMINATION OF DRUG
FIRST FEW TERMINOLOGIES:
ELIMINATION
CLEARANCE (CL)
ELIMINATION RATE
28

29. ELIMINATION OF DRUG
(How long drug stays in body?)
TERMINOLOGIES:
1. ELIMINATION:
 SUM-TOTAL of the Processes of
“METABOLISM + EXCRETION” of drug
 THESE PROCESSES HELP TO “CLEAR” the PLASMA
of its Drug Content
 DESCRIPTIVE TERM helped to evolve the term
 “CLEARANCE”
29

30. ELIMINATION OF DRUG – (How long drug stays in body?)
2. CLEARANCE (CL):
If Plasma Conc. = 2 µg/mL & Drug
Removed = 400 µg/min
 Vol. of Plasma totally “Cleared” of drug
=400÷2 = 200 mL/min  Clearance
 CL is defined as the “VOLUME” of Plasma / Blood
which is (Theoretically) completely cleared of its drug
PER UNIT TIME
 Expressed as L/hr/70 kg (or mL/min/70 kg)
 Many organs may participate in clearance
 So, unless specified, CL means CLTOTAL i.e. Cleared by
All Organs
 CLTOTAL = CLHEPATIC + CLRENAL + etc. + etc….. 30

31. ELIMINATION OF DRUG
(How long drug stays in body?)
TO SUMMARIZE THE TERMINOLOGIES:
 ELIMINATION: Descriptive term; Includes Two
Processes  drug Metabolism & Excretion
 CLEARANCE (CL): What Volume of plasma is cleared
of its drug content per Unit Time
 ELIMINATION RATE: What Amount from the
administered dose is eliminated per Unit Time
31

32. 1A. SINGLE I.V. DOSE (Bolus)
UNDERSTANDING DRUG’S BEHAVIOR IN
BLOOD & BODY?
How Long the Dose Stays in the Body (or In
How Much Time is the Dose “Nearly Totally
Eliminated”)
32
ELIMINATION OF 1ST ORDER DRUGS WHEN SINGLE I.V.
DOSE IS GIVEN (as Bolus)

33. 1A. SINGLE I.V. DOSE – GRAPHIC CALCULATION OF TIME NEEDED FOR
“NEAR TOTAL” ELIMINATION OF A DOSE?
Plasma Con. Falls to ½ its initial level:
from 3216 (50% Eliminated)
168 (50+25=75% Elimin)
84 (50+25+12.5% " " )
42 (50+25+12.5+6.25%
= 93.75% Elimin)
Each in 8 hr
33
Plasma Half
Life (T ½) of
Drug = 8 hr
CPLASMA fell 93.75% (32 to 2 µg/ml) in 4 x T ½ (32 hr)
I.V. DRUG
DISTRIBUTION
[α] PHASE
ELIMINATION
[β] PHASE
0 4 8 12 16 20 24 28 32 36
TIME (HOURS)
16
2
8
4
1
64
32
Plasma
Log-Concentration
(µg/mL)
8 hr
8hr
8hr
8hr

34.  PLASMA HALF LIFE (T ½ ) OF DRUG: Time needed
for Plasma Concentration to decline to HALF its
Initial Value (it means 50% of the Dose
present in body at that time has been
eliminated)
 In 4xT½ 93.75% (~94%) Dose Eliminated
(only ~6% Dose remains in body)
 In 5xT½ 96.875% (~97%) Dose Eliminated (only ~3%
Dose remains in body)
 In 4-5 Half Lives “NEAR TOTAL” (94-97%) Dose is
Eliminated (Washed out) from the Body  “WASH
OUT TIME” 34
TIME NEEDED FOR ELIMINATION OF A DOSE
& PLASMA HALF LIFE (T ½)

35. Pharmacokinetics-Spot-1
Bioavailability (F) for the following
2 drugs is-
Propranolol 26%
Atenolol 56%
Q. What is the ONE MOST IMPORTANT Reason for
LOW Bioavailability of Propranolol?
Answer: First Pass Metabolism (or Pre-Systemic
Metabolism)

36. Pharmacokinetics-Spot-2
Vd (Volume of Distribution) for Digoxin is 500
Liters (per 70 kg.)
Q.1. Where in the body is most of the drug
present?
Q.2. Can Dialysis be useful in treating patient
with Digoxin overdose toxicity?
Answer: Q.1. In Tissues;
Q.2. No

37. Pharmacokinetics-Spot-3
For Theophylline
Desired Plasma Concentration (C)
= 10 mg/L
Volume of Distribution (Vd)
= 35 L (per 70kg)
Q. Calculate the Dose (needed) of Theophylline.
Answer: Dose = Vd x C i.e. 35x10=350 mg

38. Pharmacokinetics-Spot-4
FOR ATENOLOL-
DESIRED PLASMA CONCENTRATION (C) = 1mg/L
VOLUME OF DISTRIBUTION (Vd) = 67L ( per 70kg)
Q. Calculate the Dose (needed) of Atenolol.
Answer: Dose = Vd x C i.e. 67x1=67 mg

39. Pharmacokinetics-Spot-5
Drug 'X' was given in 20 mg Bolus Dose.
Plasma concentration at Time Zero (C0) was
found to be 5 mg/L
Q. What is the Vd (Volume of Distribution) for Drug
'X‘?
Answer: Vd = Dose/C i.e. 20/5 = 4 Liters

40. Pharmacokinetics-Spot-6
Two Samples 'A' & 'B', of the same drug showed following
absorption data-
A B
‘F' (Bioavailability) 56% 57%
T-max (time to reach 20 min 48 min
peak conc.)
Q.1 Are the samples 'A' & 'B‘ Bioequivalent
or Bio-inequivalent?
Q.2 Why/ Why not (few words-maximum one line)?
Answer: Q.1- Bio-inequivalent
Q.2- Differing Tmax, though AUC nearly
same.

41. Pharmacokinetics-Spot-7
For Paracetamol-
CL (Clearance) = 20 L/ hr
'C' (Plasma concentration) = 15 mg/L
Q. Calculate "Elimination Rate" of Paracetamol.
Answer:
Elim Rate = CLxC
= 20x15
= 300 mg/hr

42. Pharmacokinetics-Spot-8
Ciprofloxacin (T ½ = 4.1hr) is to be given for few
days to a patient.
Q. How much time will be needed for Ciprofloxacin
to reach the Steady State Concentration (Css)?
Answer:
4-5 T ½ needed;
i.e. 4.1x 4 or 5
= 16.4 to 20.5 hr

43. Answers:
Spot 1: First Pass Metabolism (or Pre-Systemic Metabolism)
Spot 2: Q.1. In Tissues;
Q.2. No
Spot 3: Dose = Vd x C i.e. 35x10=350 mg
Spot 4: Dose = Vd x C i.e. 67x1=67 mg
Spot 5: Vd = Dose/C i.e. 20/5 = 4 Liters
Spot 6: Q.1- Bio-inequivalent
Q.2- Differing Tmax, though AUC nearly same.
Spot 7: Elim Rate = CLxC
= 20x15 = 300 mg/hr
Spot 8: 4-5 T ½ needed; i.e. 4.1x 4 or 5= 16.4 to 20.5 hr

44. CLINICAL PHARMACOKINETICS
44
BLOOD / PLASMA CONCENTRATION
DEPENDS ON
HOW MUCH DRUG
COMES INTO
BLOOD FROM
SITE OF
ADMINISTRATION
HOW DRUG
DISTRIBUTES
WITHIN BODY
ELIMINATION
PATTERN OF
THE DRUG

45. CLINICAL PHARMACOKINETICS
45
BLOOD / PLASMA CONCENTRATION
AMOUNT
ABSORBED
• BIOAVAIL-
ABILITY (F)
DISTRIBUTION
• VOLUME OF
DISTRIBUTION
[Vd or AVd]
ELIMINATION
• HALF LIFE

46. 46
Thank You
“Don’t confuse education with intelligence”