EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 1983, Yol. 8, No 2, p. 133-136 Acetylation Character of Isoniazid in the Rabbit and in Man M.F. KERGUERIS, CI. LAROUSSE, Y. LE NORMAND and M. BOURIN Department of Pharmacology, UER of Medicine, Nantes, France Received for publication: December 14, 1981 Key words : Isoniazid, acetylation, rabbit, man. SUMMARY Different pharmacokinetic parameters (Yo, Cl, t'/2) of isoniazid were determined in the rabbit and in man. The comparison of isoniazid kinetics with those of sulfadiazine in the rabbit showed that the separation into two groups of acetylators was not as marked as with sulfadiazine, plasma half-lives being similar but apparent distribution volume and clearance being much greater with isoniazid. It was difficult to compare the results obtained in animals and in man. The plasma half-life of isoniazid was about half as long as in man, but in both cases the longer half-lives were about four times as great as the shorter ones. These results suggest that in the rabbit, in a study of isoniazid used alone or with other drugs, it is preferable to search for a relationship between the isoniazid elimination rate and one effect of this drug rather than to oppose two groups of subjects. INTRODUCTION MATERIALS AND METHODS Seventy-four common male rabbits, each weighing about 2.5 kg were tested. A control blood sample was collected before administration of isoniazid. The drug (15 mg/kg) was injected intravenously into the marginal ear vein. Five blood samples were taken from the opposite marginal ear vein between 45 mn and 2h 30 after the injection. Seventy-four tuberculous patients (20 to 60 years old), with no renal or hepatic dysfunction and just beginning treatment, were also tested. Blood samples were taken at 0,2,3,4 and 5 hours after oral ad- ministration of isoniazid (5 mg/kg). Isoniazid absorption was rapid and complete (8); in the studied period, plasma levels decreased ac- cording to a first-order process. Isoniazid was deter- mined by sprectrofluorimetry, according to the Scott and Wright method (9) as modified by Thenault et al (10). The plasma half-life of isoniazid was evaluated in the rabbit and man by linear regression analyses according to a one-compartment model. The ap- parent volume of distribution (V) and the total body clearance (Cl) were calculated according to (II) Several in vivo and in vitro studies have shown that isoniazid is polymorphically acetylated in man and in the rabbit and that acetylation is the major metabolic pathway of this drug (1,2). The rabbit is the animal model used for isoniazid study, but its slow acetylator phenotype is less frequent (31%) (3) than in Caucasian man (57%) (4). Different methods have been reported for pheno- typing rabbits, essentially by using sulfadiazine (3,5, 6). Many studies have been performed with this drug in the rabbit, either using sulfadiazine in large numbers of animals or by comparing isoniazid kinetics to sulfonamide kinetics, in which case only a few animals are used (5,7). In the present study different pharmacokinetic parameters of isoniazid in the rabbit and in man were determined in order to compare isoniazid and sulfadiazine elimination in the rabbit and to evaluate this animal model with regard to man. Send reprint requests to : M.F. Kergueris, Department of Pharmacology, UER of Medicine, 44035 Nantes Cedex, France. Dose V = ----co- 0.693 t'/2 = --k- CI =kXV