Effects of cimetidine on the metabolic disposition of isoniazid in rabbits

Effects of cimetidine on the metabolic disposition of isoniazid (INH) were investigated in rabbits administered with 0.109 mmol kg^-1 of either INH, acetylisoniazid (AcINH), isonicotinic acid (INA), sodium α-ketoglutarate isonicotinoyl hydrazone (INH-K) or sodium pyruvate isonicotinoyl hydrazone (INH-P). Oral cimetidine (50 mg kg^-1 given 1 h prior to the other drugs significantly (p <0.05) decreased the systemic clearance (CL) (mean ± SEM) of INH from 95.5 ± 18.8 to 44.9 ± 9.0 ml min^-1 kg^-1. The mean formation fraction (F) of INA formed from the hydrolysis of INH and AcINH after administration of INH was significantly decreased (p <0.05) from 0.345 ± 0.033 to 0.248 ± 0.023, and that of INA formed directly from INH was also significantly decreased (p <0.05) from 0.261 ± 0.0017 to 0.179 ± 0.029. However, the mean F values of AcINH, INH-K and INH-P formed from INH were not influenced by cimetidine. The mean fraction of unchanged INH was increased significantly (p <0.05) from 0.076 ± 0.060 to 0.171 ± 0.031. An inverse linear relationship (r = -0.827, p <0.05) existed between the F of INA formed directly from INH and the fraction of unchanged INH in rabbits pretreated with cimetidine, indicating that the F of INA formed directly from INH decreased as the fraction of unchanged INH increased after cimetidine pretreatment. Furthermore, the mean F of INA after i.v. administration of AcINH also decreased significantly (p <0.05) from 0.475 ± 0.037 to 0.379 ± 0.015 in rabbits pretreated with cimetidine.