1. Introduction 2. Phases of metabolism 3. Phase-I Metabolism 4. Cytochrome P family 5. Phase –II Metabolism 6. First pass metabolism 7. Ante Drugs 8. Microsomal Enzymes induction Role of metabolism in drug discovery

1. SHORT NOTES
PC-610 (DRUG METABOLISM)
PRIYANSHA SINGH
B. Pharm, M.S.(Pharm)- Pharmacology & Toxicology

2. OUTLINE
 Introduction
 Phases of metabolism
 Phase-I Metabolism
 Cytochrome P family
 Phase –II Metabolism
 First pass metabolism
 Ante Drugs
 Microsomal Enzymes induction
 Role of metabolism in drug discovery

3. Introduction
 Biotransformation- chemical alternation of the
drug converting non polar or lipid soluble
compounds to polar/ lipid insoluble compounds.
 Consequences of biotransformation:
1. Active drug  Inactive metabolite: Pentobarbitone,
morphine, Chloramphenicol
2. Active drug  Active metabolite: Phenacetin
3. Inactive drug  Active metabolite: Levodopa

4. Prodrugs
 Inactive drug  Active metabolite
 Advantages
1. ↑ Absorption
2. Elimination of an unpleasant taste
3. ↓ Toxicity
4. ↓ metabolic inactivation
5. ↑ chemical instability
6. Prolonged/ shortened action

5. HISTORY
 Richard Tecwyn Williams
 Metabolism of
sulfonamides, benzene,
aniline, acetanilide,
phenacetin, thalidomide &
stilbestrol
 Metabolism of TNT w. r. t.
its toxicity in ammunitions Richard Tecwyn Williams

6. PHASES OF METABOLISM
Phase-1 Metabolism
Functionalization reactions
Converts drugs to more polar
metabolite by introducing/
unmasking a functional group
(-OH, -NH2, -SH)
Phase-2 Metabolism
Conjugation reactions
Subsequent reaction wherein a
covalent bond is formed
between the functional group
on the parent compound/
Phase-1 metabolite & an
endogenous substrate like
glucuronic acid, sulphate,
acetate or amino acid

7. Phases of metabolism

8. Sites of metabolism

9. PHASE-1 METABOLISM
 OXIDATION
+n of oxygen/-vely charged radical/ removal of
hydrogen/+vely charged radical.
Reactions are carried out by group of mono-
oxygenases in liver
Finally- Involves CYP450, haemoprotein, NADPH,
CYP450 reductase & O2.

10. CYTOCHROME P450 FAMILY
 Monooxygenase enzyme family
 Majorly catalyses drugs, endogenous compound oxidation
in liver, kidney, GIT, skin & lungs.
 Which require CYP heme protein, reductase, NADPH,
Phosphatidylcholine and molecular oxygen
 Occurring in smooth endoplasmic reticulum in close
association with NADPH-CYP reductase in 10:1 ratio and
this reductase enzyme is an electron source for running the
oxidative reaction cycle.

11. Electron flow in Cytochrome

12. Cytochrome P450 Enzyme Family
 Multiple CYP gene families have been identified in humans, and
they have been categorized based on the protein sequence
homology.
 Most of the drug metabolizing enzymes are found in the CYP1, 2
& 3 families.
 Frequently 2 or more enzymes can catalyse the same type of
oxidation, indicating redundant & broad substrate specificity.
 CYP3A4 very common amongst the metabolising enzymes for
drugs and it is it’s +ce which is responsible for poor
bioavailability of drugs.

13. CYP450 Enzyme family contd…

14. ROLE OF CYP ENZYMES IN HEPATIC DRUG
METABOLISM

15. Cytochrome P450 : Metabolism of Drug

16. NON CYP METABOLISM
 Monoamine Oxidase (MAO) & Diamine Oxidase (DAO)
 Mitochondrial MAO oxidatively deaminates endogenous substrates &
neurotransmitters like Dopamine, serotonin, norepinephrine,
epinephrine.
 Alcohol & Aldehyde dehydrogenase
 Non-specific enzymes found in the soluble fraction of liver used for
ethanol metabolism
 Flavin Monooxygenases
 Require molecular O2, NADPH, flavin adenosine dinucleotide (FAD)
Oxidation

17. Reduction
 Converse of oxidation
 Drugs primarily reduced in metabolism are-
chloramphenicol, chloralhydrate & halothane.

18. Cyclization & Decyclizaion
 Cyclization- formation of ring structure from straight
chain compound like proguanil
 Decyclization- Opening up of ring structure of the
cyclic drug molecule like Barbiturates, Phenytoin

19. Hydrolysis
 Cleavage of drug molecule by taking up a molecule of water
 Sites- Liver, intestines, plasma & other tissues
 Examples- Choline esters, procaine, isoniazid, pethidine,
Propantheline, Benfluorex, Pethidine, Oxytocin

20. PHASE- II/ SYNTHETIC REACTIONS
 Conjugation of a drug molecule/ its Phase1 metabolite with
an endogenous substrate to form a highly ionized polar
organic acid.
 Types of Phase II reactions
- Glucuronide
- Acetylation, Methylation
- Sulphate conjunction
- Glycine conjunction
- Glutathione conjunction
- Ribonucleoside/ nucleotide synthesis

21. Glucuronide conjunction
 Conjunction of drug/phase 1 metabolite to a-d-
glucuronic acid
 Quantitatively most importantly phase 2 pathway for
drugs & endogenous compounds
 Products are excreted by biliary route
 Requires UDP-glucuronosyltransferase (UGT) enzyme
 Compounds having –OH or –COOH functional group,
are easily conjugated with glucuronic acid derived
from glucose

22. Glucuronide conjunction contd…

23. Acetylation

24. Sulphate conjunction

26. HOFFMANN ELIMINATION

27. FIRST PASS METABOLISM
 Metabolism of a drug in between the route from the
site of absorption to systemic circulation
 Extent of FPM differs in different drug molecules.
 Drugs with various extents of FPM:-

28. ATTRIBUTES OF DRUGS WITH HIGH
FIRST PASS METABOLISM
 Drugs with ↑ FPM have a dose order- Oral dose> sublingual/ parenteral
dose.
 Due to individual variations in FPM- arises variation in oral doses of
drug.
 In liver disease patients, apparently ↑ oral bioavailability is seen.
 Oral bioavailability of the drug competing with the drug having ↑ FPM
is increased.

29. WHAT ARE ANTEDRUGS ?

30. ADVANTAGES OF ANTEDRUGS
 Localization of drug effect/ actions
 Elimination of toxic metabolites, increasing the
therapeutic index.
 Avoidance of pharmacologically active metabolites
that have long term toxicity.
 Elimination of drug interactions resulting from
metabolite inhibition of enzymes.
 Simplification of PK problems caused by multiple
active metabolites.

31. INHIBITION OF METABOLISM
 Competitively inhibit the metabolism of another drug if it
utilized the same enzyme or co factors.
 A drug may inhibit one isoenzyme while being itself a
substrate of another isoenzyme. E.g.- Quinidine is
metabolized by CYP3A4 but inhibits CYP2D6.
 Inhibition of drug metabolism occurs in a dose related
manner & can precipitate toxicity of the object drug.
 Blood flow limited metabolism. E.g.- Propranolol reduced
the rate of Lignocaine metabolism by decreasing hepatic
blood flow.

32. MICROSOMAL ENZYME INDUCTION
 Certain drugs and xenobiotics can increase the synthesis of
microsomal enzyme protein.
 Different inducers are relatively selective for certain
CYP450 families for e.g.
 Phenobarbitone, rifampicin, glucocorticoids induce CYP3A
isoenzymes.
 Isoniazids & chronic alcohol consumption induce CYP2E1.
 Induction reaches its peak in 4-14 days & is maintained till
the inducer is present in the body.

33. CONSEQUENCES OF INDUCTION
 ↓ed or ↑ed intensity of drug action.
 Autoinduction caused by a drug may increases its
tolerance.
 Precipitation of acute intermittent porphyria.
 Interfere with adjustment of dose of another drug.
 Interfere with chronic toxicity
 But induction of CYP enzymes is useful in cases of
Cushing syndrome and Congenital non haemolytic
anaemia.

34. ROLE OF METABOLISM IN
PEDIATRIC & GERIATRIC PATIENTS
 Neonates have ↓ G.F.R. & tubular secretion, hence
prolonged T1/2 of the drugs like streptomycin & penicillin.
 Hepatic metabolism in poorly developed in neonates (e.g.-
Chloramphenicol can cause grey baby syndrome if not
metabolized).
 ↓ed renal functioning, hepatic blood flow & microsomal
activity which may cause ADRs in geriatric patients

35. SIGNIFICANCE OF METABOLISM IN DRUG
DISCOVERY
 To know what CYP enzymes are responsible for
metabolism of NCEs and the route of metabolism of
NCEs
 In Vitro studies give info about
1. Metabolite profile, its stability & identification
2. CYP induction/ inhibition
3. Drug/ drug interactions studies
4. CYP isoform identification involved in drug metabolism