A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

GENETIC INFLUENCES ON DRUG METABOLISM 81
Table 14.2: Variations in drug response due to disease caused by genetic mutations
Pharmacogenetic Mechanism Inheritance Occurrence Drugs involved
variation
G6PD deficiency, favism, 80 distinct forms X-linked incomplete 10 000 000 affected Many – including 8-
drug-induced of G6PD codominant world-wide aminoquinolines, antimicrobials
haemolytic anaemia
and minor analgesics (see text)
Methaemoglobinaemia: Methaemoglobin Autosomal recessive 1:100 are heterozygotes Same drugs as for G6PD
drug-induced reductase deficiency (heterozygotes show deficiency
haemolysis
some response)
Acute intermittent
porphyria: exacerbation Increased activity of Autosomal dominant Acute intermittent type Barbiturates, cloral,
induced by drugs D-amino levulinic 15:1 000 000 in Sweden; chloroquine, ethanol,
synthetase secondary Porphyria cutanea tarda sulphonamides, phenytoin,
to defective porphyrin 1:100 in Afrikaaners griseofulvin and many others
synthesis
Number of subjects
25
20
15
10
5
0
0
2 4 6 8 10 12
Plasma isoniazid concentration (μg/mL)
Figure 14.1: Plasma isoniazid concentrations in 483 subjects six
hours after oral isoniazid (9.8 mg/kg). Acetylator polymorphism
produces a bimodal distribution into fast and slow acetylators.
(Redrawn from Evans DAP et al. British Medical Journal 1960; 2:
485, by permission of the editor.)
rapid acetylators, particularly when the drug is not given
daily, but twice weekly. In addition, slow acetylators are more
likely to show phenytoin toxicity when this drug is given
with INH, because the latter inhibits hepatic microsomal
hydroxylation of phenytoin. Isoniazid hepatitis may be
more common among rapid acetylators, but the data are
conflicting.
Acetylator status affects other drugs (e.g. procainamide,
hydralazine) that are inactivated by acetylation. Approximately
40% of patients treated with procainamide for six
months or longer develop antinuclear antibodies. Slow acetylators
are more likely to develop such antibodies than rapid
acetylators (Figure 14.2) and more slow acetylators develop
procainamide-induced lupus erythematosus. Similarly, lower
doses of hydralazine are needed to control hypertension in
slow acetylators (Figure 14.3) and these individuals are more
susceptible to hydralazine-induced systemic lupus erythematosus
(SLE).
acetylation. Individuals who acetylate the drug more rapidly
because of a greater hepatic enzyme activity demonstrate lower
concentrations of INH in their blood following a standard dose
than do slow acetylators. Acetylator status may be measured
using dapsone by measuring the ratio of monoacetyldapsone to
dapsone in plasma following a test dose.
Slow and rapid acetylator status are inherited in a simple
Mendelian manner. Heterozygotes, as well as homozygotes,
are rapid acetylators because rapid metabolism is autosomal
dominant. Around 55–60% of Europeans are slow acetylators
and 40–45% are rapid acetylators. The rapid acetylator phenotype
is most common in Eskimos and Japanese (95%) and
rarest among some Mediterranean Jews (20%).
INH toxicity, in the form of peripheral neuropathy, most
commonly occurs in slow acetylators, whilst slower response
and higher risk of relapse of infection are more frequent in
SULPHATION
Sulphation by sulfotransferase (SULT) enzymes shows polymorphic
variation. SULT enzymes metabolize oestrogens,
progesterones and catecholamines. The polymorphic forms
have reduced activity and contribute to the considerable
variability in metabolism of these compounds.
SUXAMETHONIUM SENSITIVITY
The usual response to a single intravenous dose of suxamethonium
is muscular paralysis for three to six minutes. The
effect is brief because suxamethonium is rapidly hydrolysed
by plasma pseudocholinesterase. Occasional individuals
show a much more prolonged response and may remain