Thesis (Ph. D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1989. / Includes bibliographical references (leaves 162-174).

Isoniazid (INH), one of the most effective agents in the treatment and prophylaxis of tuberculosis associated with a mild increase in liver transaminases in up to 20% of treated patients and severe hepatotoxicity in up to 2% of treated patients. Since the 1970's, a number of studies have been reported on the mechanism of INH-induced hepatotoxicity. The original studies in rats suggested that the hepatotoxic effect of INH was due to the microsomal metabolism of acetylhydrazine (AcHz, a metabolite of INH) to a reactive intermediate. More recently other workers have been unable to reproduce the original results in the rat, or other mechanistic models have been proposed. Therefore, it is necessary to establish a reproducible animal model which resembles INH hepatotoxicity in the human being. In these experiments,, male New Zealand white rabbits were used, and divided into 12 treatment groups of 6-8 rabbits each. Serum argininosuccinate lyase (ASAL) levels and histological changes in liver slides were chosen as indices of hepatotoxicity. After the determination of acetylator phenotype for each rabbit, INH and its metabolites, acetylisoniazid (AcINH), hydrazine (Hz) and AcHz were administered in a two-day regimen orally or subcutaneously. The results showed that the serum ASAL level in rabbits is a sensitive and specific enzyme marker which parallels the incidence of hepatic necrosis seen on histology. The serum ASAL control values 4.3±2.6 (SD) Takahara units were maintained until about 24 hrs after the first challenge of INH in the two-day regimen (0.36+3x0.26 mmol/kg/dx2d, s.c.); peak values of up to 2674 Takahara units occurred at about 72 hrs. No significant difference between the toxicity of INH given orally and subcutaneously was detected. Phenobarbital (PB) (0.1 mg/kgx3d, i.p.) pretreatment increased the elevation of serum ASAL level caused by INH (0.36+3x0.26 mmol/kg/dx2d, p.o.) significantly (p<0.05, F test) compared with the group without PB pretreatment. The 65 experimental rabbits were classified into populations of acetylator phenotype by measuring their acetylation rate of sulfamethazine (SMZ): fast acetylators with a SMZ t[formula omitted] of 12.8±4.4 (SD) (n=54) and slow acetylators with a SMZ t[formula omitted] of 50.3±10.4 (SD) (n=ll). Among the rabbits challenged with INH (0.36+3x0.26 mmol/kg/dx2d, p.o. or s.c.) with or without PB pretreatment, no correlation was found between the peak serum ASAL values and acetylation rate represented by SMZ t[formula omitted (r=0.05, n=18). This lack of this correlation was also present in rabbits challenged with AcINH and Hz. Among INH and its metabolites, AcINH, Hz and AcHz, Hz is the most potent hepatotoxin. Its effect is dose-dependent over the dose range (0.10+3x0.07, 0.14+3x0.10 and 0.19+3x0.14 mmol/kg/dx2d, p.o.). AcHz (0.36+3x0.26 mmol/kg/dx2d, s.c.), produced no significant hepatotoxic effect, which is contradictory to the results reported by other authors. AcINH (0.28+3x0.20 mmol/kg/dx2d, s.c, 0.42+3x0.30 mmol/kg/dx2d, s.c. or p.o.) had a intermediate hepatotoxic effect which is similar to that of INH. The results showed that (1) the rabbit is a reproducible animal model for studying INH hepatotoxicity; (2) the release of ASAL to serum and pathological changes resemble that seen in human beings; (3) the hepatotoxicity of INH is potentiated by PB pretreatment which is in accordance with the evidence in human beings of an increased risk in the presence of microsomal enzyme inducers; (4) the acetylation rate does not affect the hepatotoxicity of INH; (5) among the metabolites tested, Hz was most potent. These data indicate that the hypothesis that INH hepatotoxicity is due to microsomal metabolism of AcHz is probably incorrect. We think that it is more likely that Hz is responsible. Further studies are required to elucidate the exact mechanism in the rabbit model. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

Bibliography: leaves 162-174.

Bibliography: leaves 162-174. / xiv, 177 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1989