A Textbook of Clinical Pharmacology and Therapeutics

rapid acetylators, particularly when the drug is not given

daily, but twice weekly. In addition, slow acetylators are more

likely to show phenytointoxicity 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. Approxi-

mately 40% of patients treated with procainamidefor six

months or longer develop antinuclear antibodies. Slow acety-

lators 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 hydralazineare needed to control hypertension in

slow acetylators (Figure 14.3) and these individuals are more

susceptible to hydralazine-induced systemic lupus erythe-

matosus (SLE).

SULPHATION

Sulphation by sulfotransferase (SULT) enzymes shows poly-

morphic 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 suxa-

methoniumis muscular paralysis for three to six minutes. The

effect is brief because suxamethoniumis rapidly hydrolysed

by plasma pseudocholinesterase. Occasional individuals

show a much more prolonged response and may remain

GENETICINFLUENCES ONDRUGMETABOLISM 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

0

25

20

15

10

Number of subjects

5

0

246

Plasma isoniazid concentration (μg/mL)

81012

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 Journal1960; 2 :
485, by permission of the editor.)

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
usingdapsoneby measuring the ratio of monoacetyldapsone to
dapsonein 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 pheno-
type 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