A Textbook of Clinical Pharmacology and Therapeutics

Heterozygotes are unaffected carriers and represent about 4%

of the population.

GENETIC INFLUENCES ON DRUG

DISPOSITION

Several genotypic variants occur in the drug transporter pro-

teins known as ATP binding cassette proteins (ABC proteins).

The best known is P-glycoprotein now renamed ABCB1. This

has several polymorphisms leading to altered protein expres-

sion/activity. Effects of drug transporter polymorphisms on

drug disposition depend on the individual drug and the

genetic variant, and are still incompletely understood.

GENETIC INFLUENCES ON DRUG ACTION

RECEPTOR/DRUG TARGET POLYMORPHISMS

There are many polymorphic variants in receptors, e.g. oestro-

gen receptors, β-adrenoceptors, dopamine D 2 receptors and

opioidμ receptors. Such variants produce altered receptor

expression/activity. One of the best studied is the β 2 -adreno-

ceptor polymorphism. SNPs resulting in an Arg-to-Gly amino

acid change at codon 16 yield a reduced response to salbuta-

molwith increased desensitization.

Variants in platelet glycoprotein IIb/IIIa receptors modify

the effects of eptifibatide. Genetic variation in serotonin

transporters influences the effects of antidepressants, such

asfluoxetineandclomiprimine. There is a polymorphism

of the angiotensin-converting enzyme (ACE) gene which

involves a deletion in a flanking region of DNA that controls

the activity of the gene; suggestions that the double-deletion

genotype may be a risk factor for various disorders are

controversial.

WARFARIN SUSCEPTIBILITY

Warfarininhibits the vitamin K epoxide complex 1 (VKORC1)

(Chapter 30). Sensitivity to warfarinhas been associated with

the genetically determined combination of reduced metabolism

of the S-warfarin stereoisomer by CYP2C9 *2/*3 and *3/*3

polymorphic variants and reduced activity (low amounts) of

VKORC1. This explains approximately 40% of the variability in

warfarindosing requirement. Warfarinresistance (requirement

for very high doses of warfarin) has been noted in a few pedi-

grees and may be related to poorly defined variants in CYP2C9

combined with VKORC1.

FAMILIAL HYPERCHOLESTEROLAEMIA

Familial hypercholesterolaemia (FH) is an autosomal disease

in which the ability to synthesize receptors for low-density

paralysed and require artificial ventilation for two hours or
longer. This results from the presence of an aberrant form of
plasma cholinesterase. The most common variant which
causessuxamethoniumsensitivity occurs at a frequency of
around one in 2500 and is inherited as an autosomal recessive.

82 PHARMACOGENETICS

I I I I

I I Slow acetylators

Time to conversion (months)

Percentage of patients

with antinuclear antibodies

I I

I I

I I 9

9

9

0

0

20

40

60

80

100

2 4 6 8 10 12 77

9

9

8

Rapid acetylators

8

Figure 14.2:Development of procainamide-induced antinuclear
antibody in slow acetylators () and rapid acetylators () with
time. Number of patients shown at each point. (Redrawn with
permission from Woosley RL et al. New England Journal of
Medicine1978; 298 : 1157.)

0.4

0.3

0.2

0.1

Slow

acetylators

Fast

acetylators

0

Serum concentration

dose

μg/mL

mg/kg/day

(

(

Figure 14.3:Relationship between acetylator status and dose-
normalized serum hydralazine concentration (i.e. serum
concentration corrected for variable daily dose). Serum
concentrations were measured one to two hours after oral
hydralazine doses of 25–100 mg in 24 slow and 11 fast
acetylators. (Redrawn with permission from Koch-Weser J.
Medical Clinics of North America1974; 58 : 1027.)