ADME 2

Drug Metabolism
MEDSCI 303
Lecture 5
James W. Paxton
Dept of Pharmacology
& Clin Pharmacology

Learning Objectives
To describe the various processes by which a
drug may be metabolized
To understand the outcomes of drug
metabolism
To comprehend the factors that influence the
rate and extent of drug metabolism and the
possible impact on drug therapy
To comprehend the part played by CYPs in
drug metabolism

Drug Metabolism results in:

Drug

metabolising

More
polar
metabolite
enzyme

Less

likely to diffuse into cells to reach receptors

Favours increased excretion in urine or bile
Usually abolishes activity and terminates drug action,
but :
Can

promote activity - prodrug

eg, acetylsalicylate salicylate

Codeine morphine

change in activity eg, diazepam -> nordiazepam

Produce toxic metabolites eg, paracetamol
No

Drug metabolism reactions :

Phase 1 (addition or uncovering of a reactive group)
Oxidation
Reduction
Hydrolysis

Phase 2

Makes the molecule more

susceptible to Phase 2 reactions

(conjugation of endogenous molecule with drug)

Glucuronide
Sulphate
Amino

acids, GSH
Acetylation

Makes the molecule more

polar, and also ideal
substrates for active
transport & excretion

Oxidation is the most important reaction

for Phase 1 metabolism of drugs

Most important oxidative enzymes are the

cytochrome P450 dependent mixed function oxidases
(CYPs) (located on the smooth endoplasmic reticulum)

Family

of closely related isozymes (at least 20 gene families in

humans) of which CYP1, CYP2 and CYP3 encode
enzymes involved in most drug metabolism.

Requires

O2, NADPH and cytochrome P450

reductase.
DRUG + O2 + H+ + NADPH

Oxidised drug + H2O + NADP+

CYP nomenclature
CYP 3 A 4

cytochrome

isoform
p450

Subfamily
Family

(>60% aminoacid homology)

(> 40% aminoacid homology)

Localization of Drug-metabolising
CYPs
Hepatic
1A2 (13%)
2A6 (4%)
2B6 (<1%)
2C (18%)
2D6 (2.5%)
2E1 (7%)
3A4 (28 70%)

Extra-hepatic

gut wall, lung

gut wall
lung, placenta
gut wall, kidney,
lung, placenta,
uterus

Common CYPs and example substrates

CYP

Substrates

CYP1A1/2

Procarcinogens & promutagens, caffeine,

theophylline (induced by benzo[a]pyrenes in
cigarette smoke & BBQ meat)

CYP2C9

R-mephenytoin, S-warfarin, omeprazole

CYP2D6

Debrisoquine, sparteine, codeine

various -blockers, tricyclic antidepressants
(inhibited by quinidine, fluphenazine, fluoxetine)

CYP3A4

Cyclosporine, nifedipine, erythromycin,

terfenadine, theophylline, testosterone
(inhibited by quinolones, ketoconazole,
erythromycin & grapefruit juice)
(induced by rifampicin, glucocorticoids & barbiturates)

Induction of CYP enzymes

Enzyme

synthesis initiated within 24 h of

exposure, increasing over 3 5 days

Effect

decreases over 1 3 weeks after inducing

agent is discontinued

Environmental Factors:
Cigarette smoking; eating BBQ meat, cruciferous veges,

high protein diet, ethanol, exposure to insecticides (DDT,

Lindane) & polychlorinated biphenyls (PCBs)

Other drugs:
Barbiturates, phenytoin, carbamazepine, rifampicin &

dexamethasone

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Inhibition of CYP enzymes

Rapid

onset within 1 day

Exaggerated

toxicity

response with increased risk of

Competitive reversible inhibitors:

Cimetidine, ketoconazole, quinolone antibiotics,

oestrogens, grapefruit juice

Heavy metals: (complex

Lead, cadium, mercury

with CYPs)

Phase 2 conjugations

11

Glucuronidation
by uridine glucuronosyl transferases (UGT) (microsomal)
transfers a glucuronic acid (MW =177) residue from uridine diphosphate
glucuronic acid (UDPGA) to steroids , bilirubin and drugs

Sulphation
Sulphotransferases (cytosol)
l Cofactor 3-phosphoadenosine 5-phosphosulphate (PAPS)

Amino-acid/peptide

conjugation

With glycine or glutamine or glutathione (GSH) (Glut-Cyst-Gly)

l Glutathione S-transferases (GST) adds a tripeptide GS! (MW = 307) onto
electron deficient C, N, S or O atom (i.e.,electrophiles)

Acetylation
N-acetyl transferase (cytosol)
l Requires Acetyl CoA
l Sulphonamide drugs

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Metabolism of phenytoin :
O

Phase 1

NH

HN

Hydroxylation by
CYP 2C9

Phase 2

Highly lipophilic
HN

OH

NH

HO

Conjugation by UDP glucuronosyl

transferase

NH

COOH
OH
H
H
OH H
O
HO

HN

Slightly
soluble
in water

Very
soluble
in water

COOH
OH
H
H
OH H
UDP
HO
H
OH
Uridine diphosphate glucuronide

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Overlapping variables that influence
rate & extent of drug metabolism :

Organ function
Liver ; Renal
Cardiovascular
Endocrine ; GI
Age
Sex
Pregnancy
Circadian
rhythms

Patient
Genetic
constitution
Environment
Diet
Cigarettes
Alcohol
Exercise

Diseases & Drugs

Infections
Malignancy
Enz inducers
Enz inhibitors

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Plasma phenytoin concentrations in a group of

ambulatory patients, all receiving 300 mg/day.
>30
Plasma
Phenytoin
(mcg/ml)

(15%)

20-24.9

Therapeutic
Range (30%)

10-14.9

(55%)

<5.0
0
One dose size
does not fit all !

20

40

Percent of Patients
(Data from: Koch-Weser J. Eur J Clin Pharmacol 9:1-8, 1975)

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Drugs fate after metabolism ?

Lungs

Heart
Other tissue
eg. brain

Arterial
blood

Kidney

Renal excretion
Gut wall

Faecal
excretion

Venous
blood

Gut lumen

Liver
Biliary secretion

metabolites