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
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BIOTRANSFORMATION UNIT -1 DRUG METABOLISM (1).pptx
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
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.
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.
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
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.
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