Clinical Pharmacokinetics of Isoniazid

Abstract

The pharmacokinetics of isoniazid in man are described. Pronounced interindividual variation in circulating isoniazid concentration and clearance which occur after dosing with the drug are associated with hereditary differences in the acetylator status. The variations in rate of isoniazid inactivation and elimination in different (rapid and slow) acetylator phenotypes are primarily due to differences in the rate of acetylation of isoniazid by a genetically controlled polymorphic N-acetyltransferase in liver and small intestine. An appreciable 'first-pass' effect is observed following oral isoniazid administration, particularly in the rapid acetylator phenotype. Liver disease can cause a significant prolongation in the clearance of isoniazid; in the acutely ill patient, the prolongation correlates most closely with serum bilirubin elevation, although the degree of prolongation is less important than the intrinsic genetic difference between acetylator phenotypes. The effect of renal impairment on isoniazid excretion is relatively unimportant, even in slow acetylators. Methods for monitoring blood and urine concentrations of isoniazid and for acetylator phenotype determination which are convenient for the patient and clinician are available. Implications of phenotype differences in acetylator status for the optimal management of tuberculosis with isoniazid are considered. Attempts to devise new isoniazid formulations for this purpose are being evaluated.

Hydralazine‐induced peripheral neuropathy seen in a Japanese slow acetylator patient.

“…According to the criteria reported previously (Tiitinen, Mattila & Eriksson, 1973;Weber & Hein, 1979) (Ellard & Gammon, 1976;Weber & Hein, 1979) were 4.43 ,tg/ml, 0.3 and 0.78 in this patient, respectively. The respective values (mean + s.e.…”

“…Such a small value has also been involved in the data reported by other investigators (Jenne, MacDonald & Mendoza, 1961;Ellard, Gammon & Tiitinen, would differ between slow and rapid acetylators (Weber & Hein, 1979 In this case it is probably suggested that the hydralazine administration was causally correlated to the aetiology of the development of peripheral neuropathy according to the definition of cause-effect relationship between a drug and its adverse reaction proposed by Karch & Lasagna (1975). This is the first report in a slow acetylator residing in the region where rapid acetylators highly predominate in general population (Sunahara et al, 1961;Lunde et al, 1977;Weber & Hein, 1979). This was not unexpected as has been suggested by other investigators (Lunde et al, 1977) that slow acetylators are more prone to develop INH-induced peripheral neuropathy.…”

The effect of acetylator phenotype on the disposition of aminoglutethimide.

“…isoniazid (Weber & Hein, 1979), sulphamethazine (Evans & White, 1964), hydralazine (Reece et al, 1980). For DDS, acetylation is a minor elimination pathway and although the ratio of MADDS to DDS accurately reflects acetylator phenotype, the half-life is similar in fast and slow acetylators (Gelber et al, 1971).…”

Polymorphism of debrisoquine hydroxylation among Finns and Lapps.

“…In basal conditions drug metabolic reactions are under genetic control and often exhibit polymorphism in the population. The phenotypes of slow and rapid acetylators are well established in different ethnic groups (Weber & Hein, 1979). More than 60% of the Finns belong to the slow acetylator phenotype whereas Lapps are mostly (70-90%) rapid acetylators (Tiitinen et al, 1973).…”