A Textbook of Clinical Pharmacology and Therapeutics

82 PHARMACOGENETICS
Percentage of patients
with antinuclear antibodies
100
80
60
40
20
0
0
I I
I I
I I
I I
9
I I
Slow acetylators
9
I I 9
2 4 6 8 10 12 77
Time to conversion (months)
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
causes suxamethonium sensitivity occurs at a frequency of
around one in 2500 and is inherited as an autosomal recessive.
9
9
8
Rapid acetylators
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
Medicine 1978; 298: 1157.)
((
μg/mL
Serum concentration
mg/kg/day
dose
0.4
0.3
0.2
0.1
0
Slow
acetylators
Fast
acetylators
Figure 14.3: Relationship between acetylator status and dosenormalized
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 America 1974; 58: 1027.)
8
Heterozygotes are unaffected carriers and represent about 4%
of the population.
GENETIC INFLUENCES ON DRUG
DISPOSITION
Several genotypic variants occur in the drug transporter proteins
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 expression/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. oestrogen
receptors, β-adrenoceptors, dopamine D 2 receptors and
opioid μ receptors. Such variants produce altered receptor
expression/activity. One of the best studied is the β 2-adrenoceptor
polymorphism. SNPs resulting in an Arg-to-Gly amino
acid change at codon 16 yield a reduced response to salbutamol
with 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
as fluoxetine and clomiprimine. 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
Warfarin inhibits the vitamin K epoxide complex 1 (VKORC1)
(Chapter 30). Sensitivity to warfarin has 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
warfarin dosing requirement. Warfarin resistance (requirement
for very high doses of warfarin) has been noted in a few pedigrees
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