A Textbook of Clinical Pharmacology and Therapeutics

80 PHARMACOGENETICS

Table 14.1:Variations in drug metabolism/pharmacodynamics due to genetic polymorphisms

Pharmacogenetic Mechanism Inheritance Occurrence Drugs involved

variation

Phase I drug metabolism:

Defective CYP2D6 Functionally defective Autosomal recessive 7–10% Caucasians, Originally defined by

1% Saudi Arabians, reduced CYP2D6

30% Chinese debrisoquine hydroxylation;

Beta blockers: metoprolol;

TCAs: nortriptyline; SSRIs:

fluoxetine; Opioids: morphine;

Anti-dysrhythmics: encainide

Ultra-rapid metabolism:

CYP2D6 Duplication 2D6 1–2% Caucasians, Rapid metabolism of 2D6

30% Egyptians drug substrates above

Phase II drug metabolism:

Rapid-acetylator status Increased hepatic Autosomal dominant 45% Caucasians Isoniazid; hydralazine; some

N-acetyltransferase sulphonamides; phenelzine;

dapsone; procainamide

Impaired glucuronidation Reduced activity UGT1A1 7–10% Caucasians Irinotecan (CPT-11)

Abnormal pharmacodynamic responses:

Malignant hyperthermia Polymorphism in Autosomal dominant 1:20 000 of Some anaesthetics, especially

with muscular rigidity ryanodine population inhalational, e.g. isoflurane,

receptors (RyR1) suxamethonium

Other:

Suxamethonium Several types of Autosomal recessive Most common Suxamethonium

sensitivity abnormal plasma form 1:2500

pseudocholinesterase

Ethanol sensitivity Relatively low rate of Usual in some ethnic Orientals Ethanol

ethanol metabolism by groups

aldehyde dehydrogenase

CYP2C9POLYMORPHISM (TOLBUTAMIDE
POLYMORPHISM)

TheCYP2C9gene is found on chromosome 10 and six poly-
morphic variants have been defined. Pharmacogenetic vari-
ation was first described after the finding of a nine-fold range
between individuals in the rate of oxidation of a sulphony-
lurea drug, tolbutamide. CYP2C9 polymorphisms cause
reduced enzyme activity, with 1–3% of Caucasians being poor
(slow) metabolizers. Drugs metabolized by CYP2C9 are elim-
inated slowly in poor metabolizers, who are therefore suscep-
tible to dose-related ADRs. Such drugs include S-warfarin,
losartanandcelecoxib, as well as the sulphonylureas.

CYP2C19POLYMORPHISM

CYP2C19is found on chromosome 10 and four polymorphic
variants have been defined. These polymorphisms produce

reduced enzyme activity and 3–5% of Caucasians and 15–20%

of Asians have genotypes which yield a poor (slow) metabo-

lizer phenotype. Such patients require lower doses of drugs

metabolized by the CYP2C19 enzyme. These include proton

pump inhibitors (omeprazole,lansoprazole,pantoprazole)

and some anticonvulsants, e.g. phenytoin,phenobarbitone.

PHASE II DRUG METABOLISM

AC ET Y LATO R STAT U S (N-ACETYLTRANSFERASE-2)

Administration of identical doses (per kilogram body weight)

ofisoniazid(INH), an antituberculous drug, results in great

variation in blood concentrations. A distribution histogram of

such concentrations shows two distinct groups (i.e. a ‘bimodal’

distribution; Figure 14.1). INH is metabolized in the liver by