Drug Metabolism

Presented by: Jennica Marie B. Lauron, RPh

Drug Metabolism / Biotransformation

• The chemical modification of drugs with the

overall goal of getting rid of the drug
• Enzymes are typically involved in metabolism

Biotransformation is the enzyme catalysed

chemical alteration of the drug in the body.
Drug Metabolism

Metabolism More polar Excretion

Drug (water soluble)
Drug
Sites of Drug Metabolism
• Metabolism occurs in many tissues
• E.g. brain, kidney, lung, plasma, intestine.

But mostly in the liver because …

all of the blood in the body passes through
the liver.
 Intravenous
Administrati
on
Oral
Administrati
on

Biotransformation Live
r

Intesti
nes
 Consequences Of Metabolism

Drug metabolism != Drug inactivation

• The metabolite may have…
No or reduced activity (inactivation)
Most drugs and their active metabolite are rendered inactive.
Examples- Phenobarbitone Morphine
Chloramphenicol Propranolol.

Phenobarbitone Hydroxyphenobarbitone
(inactive)
Consequences Of Metabolism
The metabolite may have…
Equal activity to the drug
Many drugs have been found to be partially converted to
active metabolite.
Examples-

Active drug Active metabolite

Diazepam Oxazepam
Codeine Morphine
Consequences Of Metabolism
The metabolite may have…
Increased activity (Prodrug)

Prodrugs refers to precursor drug that in itself has little or no

biological activity and is metabolised to pharmacologically active
metabolite.

Features:
• Toxic properties not seen with the parent drug
• Stable drug
• Better PK profile and bioavailability.
First Pass Effect
• Biotransformation of drug by liver or gut enzymes
before compound reaches systemic circulation
• Results in lower systemic bioavailability of parent
compound, diminished therapeutic response.
• First pass effect may be bypassed if the drug is
administered IV or Sublingually.
Examples: Propafenone, Isoniazid,
Propanolol
Drug Metabolizing enzymes
• Microsomal
• Non-microsomal
• Non –enzymatic biotransformation
 • Microsomal cytochrome P450,
monooxygenase family of enzymes,
which oxidize drugs.
• Location-smooth endoplasmic reticulum
in Liver, Kidney, intestinal mucosa, and
lungs.
Microsomal
Enzymes • They catalyze:
• Oxidation, reduction, hydrolysis (phase I
reactions)
• Glucuronide conjugation (phase II
reactions)
 Cytochrome P450

• Microsomal enzyme ranking first among Phase I

enzymes with respect to catalytic versatility
• Heme-containing proteins
Complex formed between Fe2+ and CO absorbs
light maximally at 450 (447-452nm) Overall
reaction proceeds by catalytic cycle:

RH + O2+ H++ NADPH ROH + H2O + NADP+

CYP 450 System
Definitions
• Substrate:
Drug is metabolised by the enzyme system

• Inducer:
Drug that will increase the synthesis of CYP450
enzymes

• Inhibitor
Drug that will decrease the metabolism of a substrate
Cytochrome P450 expression

• Specific forms of CYP 450 are classified into

• Families designated by numbers…
• Subfamilies designated by letters… based on amino
acid sequences
• Genes by another number
• At least 15 P450 enzymes identified in human liver
microsomes
CYP450 Nomenclature
Family

CYP2D6
Sub-Family Individual Gene
Enzyme characteristics
% of drugs metabolised by enzyme

• 3A4 60%
• 2D6 25%
• 1A2 15%
• 2C9 Small no. but significant interactions

• 2C19 Small no. but significant interactions

• 2E1 ?
Cytochrome P450 expression
• Variation in levels, activity due to:
•Genetic polymorphism
•Environmental factors:
•Inducers, inhibitors, disease
•Multiple P450’s can catalyze same reaction
•A single P450 can catalyze multiple pathways
 • Location :
• Cytoplasm, mitochondria of hepatic cells.
• Examples :
• Monoamine oxidases (MAO), Esterases, Amidases,
Transferases, Conjugases
• Reaction catalysed are all Phase II reactions
except_?...._____
Non-microso • These are noninducible
mal Enzymes • May show genetic variations
 •Hoffman’s Elimination
• Example: some drugs like atracurium
(skeletal muscle relaxant) are
metabolized in plasma through
molecular rearrangement without
Non –enzymatic involvement of enzyme action.
bio-transformation
BIOTRANSFORMATION REACTIONS

Nonsynthetic / Phase I:
Metabolite may be active or inactive.

Synthetic / Phase II:

Metabolite is mostly inactive (conjugation)
Comparing Phase I & Phase II
PHASE I
REACTIONS
⦿ A small polar group is either exposed on the drug or added to
the drug
• +O, -H
• Introduction of: OH, COOH, NH2, SH

⦿ Oxidation

⦿ Reduction

⦿ Hydrolysis
 OXIDATION
• substrate loses electrons

• addition of oxygen, dehydrogenation, or simply transfer of

electrons…
COMMON OXIDATION REACTIONS
• alcohol dehydrogenation
• aldehyde dehydrogenation
• alkyl/acyclic hydroxylation
• aromatic hydroxylation
• deamination
• desulfuration
• N-dealkylation
• N-hydroxylation
• N-oxidation
• O-dealkylation
• sulphoxidation
 REDUCTION
Substrate gains electrons
Occurs when oxygen content is low
Common reaction
• azo reduction
• dehalogenation
• disulfide reduction
• nitro reduction
• N-oxide reduction
• sulfoxide reduction
 HYDROLYSIS
Addition of water splits the molecule into two fragments or
smaller molecules

-OH go to one fragment and –H to other

Eg : Larger chemicals such as esters, amines, hydrazines, and

carbamates
PHASE II REACTIONS
• Conjugation

• Endogenous substance is added to the reactive site of the Phase

I metabolite

• more water-soluble
 TYPE I TYPE II
• Methylation • Peptide conjugation

• Glucuronidation • Glutathione conjugation

• Sulfation • Glycosylation

• Acetylation
COFACTORS
Type 1- Reactive/ Activated Cofactor
a)UDP- Glucuronic acid
b)PAPS
c)Acetyl CoA
d)SAM
Type 2- Reactive Xenobiotic
a)Glutathione
b) Aminoacids(glycine,glutamine,
taurine)
PRIMARY ENZYMES INVOLVED

• Glucuronosyltransferase

• Sulfotransferase

• Glutathione-S-transferase

• Acetyltransferase
 • GLUCURONIDE CONJUGATION
glucuronic acid from glucose
Sites involve substrates having O2, N2 or S bonds
Includes xenobiotics as well as endogenous substances
Reduces toxicity..(sometimes produce carcinogenic
substances)
Results to polar
Excreted: kidney or bile depending on conjugate size
 COOH COOH

O O
Glucuronyl
R – OH + O UDP O R + UDP
OH transferase OH
HO HO
OH OH
 Examples of drugs

cofactor
 SULPHATE CONJUGATION
Decreases toxicity
Result to polar products
readily excreted by urine
Sulphotransferase
PAPS limits the pathway
 GLUTATHIONE CONJUGATION
Conjugate loses glutamic acid and glycine
detoxify

Cysteine is N-acetylated to give stable mercapturic

acid derivatives
 H H
N
Glutamic H O H H
acid N
O O
O H
O H
O H
H N
+ O
H H S O
N H
H
Cysteine S O N
O
O
H O
+ H
H H
N Glutathione
Glycine O

O
H
 ACETYLATION
the water solubility of parent molecule and their excretion
Masks the functional group of parent from participating in
conjugations
Acetyl transferases
Aromatic amines or hydrazine group to amides or hydrazides
Drug deactivation
 Methylation
Makes slightly less soluble
Drug deactivation
Masks available functional groups
Types
O- methylation
N- methylation

S- methylation
ENZYME INDUCTION
 Enzyme Induction
• Several drugs (inducers) induce the growth of
smooth endoplasmic reticulum leading to enhanced
microsomal enzyme activity
✔Accelerates metabolism
✔Decrease pharmacological response of not only the
inducer itself but also of the coadministerd drug
(substrate)
• Occurs gradually over 1-2 weeks
Enzyme Induction
Enzyme inducers Enzymes induced substrates
Phenobarbitone CYP3A4 Midazolam
Phenytoin Macrolides
carbamazepine Calcium channel
blockers
Rifampicin CYP3A4 & Oral contraceptives
Phenobarbitone CYP2C9 Warrfarin
Some enzyme Inducers
• Barbiturates (3A) • St Johns Wort (3A)
• Carbamazepine • Ethanol (2E1)
(2C19, 3A) • Troglitazone (3A)
• Phenytoin (3A) • Tobacco (1A2)
• Rifampicin • Omeprazole (1A2)
(2C19, 2C9, 3A) • Nevirapine (3A)
Clinical importance
• Increased drug metabolism :
• Decreased plasma levels and therapeutic effects
of the substrate ( co administered drug)
• Increase drug activity if the metabolite is active
• Examples : OC pills , Warfarin (therapeutic
failure)
• Therapeutic use of enzyme induction
Treatment of neonatal Jaundice ; Phenobarbitone induces
foetal gluronyl transferase which catalyses conjugation of
bilirubin
Enzyme Inhibition
• Often rapid, reversible and relatively short acting.

• E.g. erythromycin and Terfanadine

• Erythromycin causes a rapid increase in plasma Terfenadine
concentration if given concurrently.

• Note: Erythromycin is a substrate and an inhibitor of

CYP 3A4
Some Enzyme Inhibitors
• Cimetidine
• Fluoxetine
• Erythromycin
• Chloramphenicol
Mnemonics
ENZYME INDUCERS ENZYME INHIBITORS
• SICKFACESCOMG
• CRAPGPS • Sodium Valproate
• Carbamazepine • Isoniazid
• Cimetidine
• Rifampin • Ketoconazole
• Fluconazole
• Alcohol (Chronic) • Acute alcoholism
• Phenytoin • Chloramphenicol
• Erythromycin
• Griseofulvin • Sulfonamide
• Ciprofloxacin
• Phenobarbital • Omeprazole
• Metronidazole
• Sulfonylureas/ Smoking • Grape Fruit Juice
Metabolism of phenytoin :