Metabolism of drugs

2.  Drug is any substance or product that is
used or is intended to be used to modify or
explore physiological systems or
pathological states for the benefit of the
recipient.
 Biotransformation means chemical alteration
of the drug in the body.
 The metabolites formed are less lipid
soluble.

3.  What does biotransformation do?
It converts lipid soluble compounds to lipid
insoluble so that they are not reabsorbed.
 Role of biotransformation:
› defensive mechanism
› increases polarity of drug molecules,
 restricts penetration through cellular
membrane
 reduces distribution
 promotes elimination

4.  Liver
 GIT
 Lungs
 Kidney
 Plasma
 Skin
 Nasal Mucosa
 Others

5.  Inactive metabolite from an active drug
 Active metabolite from an active drug
 Active metabolite from an inactive drug

6.  Phase 1 reactions
1. Mainly microsomal - oxidation
reduction
hydrolysis
2. Few non microsomal-
3. Metabolite may be active or inactive.

7.  Phase 2 reactions
1. Synthetic/Conjugation reactions
2. Can be catalysed by microsomal,
mitochondrial or cytoplasmic enzymes.
3. Metabolite – mostly inactive

8. Endogenous radical

11. RH+02+NADPH+H+ ----------------► R0H+H20+NADP+

14. OTHER
36%
CYP2D6
2%
CYP2E1
7%
CYP 2C
17%
CYP 1A2
12%
CYP 3A4-5
26%
CYP 1A2
14%
CYP 2C9
14%
CYP 2C19
11%
CYP2D6
23%
CYP2E1
5%
CYP 3A4-5
33%
RELATIVE HEPATIC CONTENT
OF CYP ENZYMES
% DRUGS METABOLIZED
BY CYP ENZYMES
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15.  Oxidation- This reaction involves addition of
oxygen /negatively charged radical or
removal of hydrogen /positively charged
radical.
 Oxidations are the most important drug
metabolizing reactions.
 Various oxidation reactions are:
hydroxylation;oxygenation at C,N or S
atoms; N or 0-dealkylation, oxidative
deamination, etc.

16.  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 02.
 More than 100 cytochrome P- 450
isoenzymes differing in their affinity for
various substrates (drugs) have been
identified.
 Eg Imipramine, diazepam, codiene,
phenytoin, barbiturates, paracetamol.

17.  Reduction- A chemical reaction in which
hydrogen s added to, or oxygen is removed
from a compound.
 Alcohols, aldehydes, quinones are reduced.
 Drugs -chloralhydrate, chloramphenicol,
halothane, warfarin.

18.  Hydrolysis -This is cleavage of drug
molecule by taking up a molecule of water.
 Ester + H20 Esterase Acid + Alcohol
 Hydrolysis occurs in liver, intestines, plasma
and other tissues.
 Examples are choline esters, procaine,
lidocaine, procainamide, aspirin, c

19.  Super family of phase I enzymes expressed at high levels
in the liver bound to ER.
 Six families of FMOs, FMO3 – most abundant in the liver.
 Metabolize nicotine, H2 receptor blocker, antipsychotics
[clozapine], antiemetics [itopride].
 Genetic deficiency  Fish odor syndrome due to lack of
metabolism of TMAO [ trimethylamine N oxide ]  TMA.
 Minor contributors to drug metabolism - produce benign
metobolites.
 Not involved in drug-drug interactions.
 Eg : Itopride metabolized by FMO3
: Cisapride metabolized by CYP3A4
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20.  Phase 2 conjugation enzymes are synthetic in nature –
result in formation of metabolite with increase in
molecular mass.
 Terminate biological activity of the drug.
 Characteristic feature – dependency on the catalytic
reaction for cofactors such as UDP-GA, & PAPS,for UGT
& SULT, which react with available functional groups on
the substrates.
 All reactions are carried out in cytosol of the cell,
exception of glucuronidation.
 Catalytic rates of phase 2 reaction are significantly faster
than rates of CYP’s.
 So rate of elimination depends on Phase 1.
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21.  Most important phase 2 reaction catalyzed by UDP-
Glucuronosyltransferases (UGTs).
 UGT2 – Greater specificity for glucuronidation of steroids.
 UGT1A1 – Glucuronidation of bilirubin.
Crigler Najjars syndrome type 1 & type 2
 Most common genetic polymorphism – Gilberts
syndrome (10% popuplation) (mutation in UGT1A1
gene).
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22.  SULT located in cytosol, metabolise various substrates.
 13 SULT isoforms identified – role in human homeostasis.
SULT1B1  catalysis of cholesterol .
SULT1A3  selective for catecholamine
SULT1E1  estrogens are sulfated
SULT2A1  DHEA
SULT1 Sulfation of phenolic molecules. Eg:-
acetaminophen and minoxidil.
 SULT1A1  Most abundant in human tissue.
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23.  The glutathione-S-transferases (GSTs) catalyze
the transfer of glutathione to reactive
electrophiles, a function that serves to protect
cellular macromolecules from interacting with
electrophiles that contain electrophilic
heteroatoms (-O, -N, and -S) and in turn
protects the cellular environment from damage.

24.  Glutathione exists in the cell as oxidized
(GSSG) or reduced (GSH) forms, and the ratio
of GSH:GSSG is critical in maintaining a cellular
environment in the reduced state.
 A severe reduction in GSH content can
predispose cells to oxidative damage.

25.  Over 20 human GSTs have been identified and
divided into two subfamilies: the cytosolic and
the microsomal forms.
 The major differences in function between the
microsomal and cytosolic GSTs reside in the
selection of substrates for conjugation;
 The cytosolic forms have more importance in
the metabolism of drugs and xenobiotics,
 Whereas the microsomal GSTs are important in
the endogenous metabolism of leukotrienes and
prostaglandins.

26. › The cytosolic N-acetyltransferases (NATs) are responsible
for the metabolism of drugs and environmental agents that
contain an aromatic amine or hydrazine group.
› NATs are among the most polymorphic of all the human
xenobiotic drug-metabolizing enzymes.
› There are two functional NAT genes in humans, NAT1 and
NAT2.
› The therapeutic relevance of NAT polymorphisms is in
avoiding drug-induced toxicities.
26

27.  NAT1 is ubiquitously expressed among most
human tissues, whereas NAT2 is found
predominantly in liver and the GI tract.

28.  Xenobiotics undergo O-, N-,S- methylation.
 N-methyltransferase are COMT, POMT, TPMT.
 The common theme among the MTs is the generation
of a methylated product, substrate specificity is high
and distinguishes the individual enzymes.
 TPMT – catalysis the S- methylation of aromatic and
cyclic sulfhydryl compounds.
 Genetic deficiency of TPMT – severe toxicities of thio
purine drugs.(Azathioprine , 6-mercaptopurine )
28

29.  Drugs on repeated administration stimulate the
growth of smooth endoplasmic reticulum.
 This induction usually reversible, leads to increased
microsomal enzyme activity.
 Therefore, metabolism is increased and
pharmacological response in decreased.
 Mostly in liver, but can also occur in intestine, lung,
placenta, kidney.

30. 1. It reduces efficacy and potency of drugs metabolized by these
enzymes.
2. It reduces plasma half-life and duration of action of drugs.
3. It enhances drug tolerance.
4. It increases drug toxicity by enhancing concentration of metabolite, if
metabolite is toxic.
5. It increases chances of drug interactions.
6. Can be used for therapeutic benefits.
Clinical importance of enzyme
induction
30

31. 31
CYP 450 enzymes and their inducers

32. It takes 3-10 days to induce and 1-3 weeks to return to normal
levels after stoppage of inducer
32
Atorvastatin

33.  One drug may inhibit the metabolism of another drug
with resultant increase in the circulating levels of the
slowly metabolised drug and prolongation of its
pharmacological effects.
 Enzyme inhibition can be of hepatic microsomal MFOs
or of enzymes having specific functions. Eg:xanthine
oxidase, monoamine oxidase.
 Rapid and usually reversible process.

34. INHIBITORS ENZYME INHIBITED Drugs affected
Cimetidine Hepatic microsomal mixed
function oxidase
Phenytoin, Warfarin, Anti Depressants,
Theophyline, Diazepam, Quinidine,
Testosterone
Sodium
valpaorate
Hepatic microsomal mixed
function oxidase
Phenytoin, phenobarbital, primidon
Erythromycin Hepatic microsomal mixed
function oxidase
Theophyline, Warfarin, carbamazepine,
cyclosporin
Disulfiran,tolbu
tamide,
metranidazole
Aldehyde dehydrogenase Alcohol,Warfarin
Carbidopa L-aromatic aminoacid
decorboxylase
L-dopa
34

35.  Adverse consequences
1. Unexpected nausea, vomiting and tremors
may occur when Theophylline is given with
erythromycin.
2. Enhanced bleeding tendency when
Dicumerol is given with cimetidine.
3. Severe respiratory depression may occur
when Morphine is given with MAOs.

36.  Therapeutically beneficial consequences
1. Increased accessibility of L-dopa in brain
when given along with carbidopa.
2. Aversion to alcohol after prior administration
of disulfiram.
3. Reversal of skeletal muscle paralysis due to
tubocurarine by neostigmine.

37.  Age
 Sex
 Species
 Race
 Genetic variations
 Nutrition and diet

38.  Metabolism normally results in the
inactivation of their therapeutic effectiveness
and facilitates their elimination.
 The extent of metabolism can determine the
efficacy and toxicity of a drug by controlling
its biological t1/2.

39.  If a drug is metabolized too quickly, it rapidly
loses its therapeutic efficacy.
 This can occur if specific enzymes involved
in metabolism are naturally overly active or
are induced by dietary or environmental
factors.

40.  If a drug is metabolized too slowly, the drug
can accumulate in the bloodstream; as a
consequence, the pharmacokinetic parameter
AUC (area under the plasma concentration-time
curve) is elevated and the plasma clearance of
the drug is decreased.
 This increase in AUC can lead to
overstimulation or excessive inhibition of some
target receptors or undesired binding to other
cellular macromolecules.

41.  While environmental factors can alter the
steady-state levels of specific enzymes or
inhibit their catalytic potential.
 The phenotypic changes in drug metabolism
are also observed clinically in groups of
individuals that are genetically predisposed
to adverse drug reactions because of
pharmacogenetic differences in the
expression of xenobiotic-metabolizing
enzymes.

42.  Before a new drug application (NDA) is filed
with the Food and Drug Administration, the
route of metabolism and the enzymes
involved in the metabolism must be known.
 As a result, it is now routine practice in the
pharmaceutical industry to establish which
enzymes are involved in metabolism of a
drug candidate and to identify the
metabolites and determine their potential
toxicity.