Isoniazid metabolism in the rabbit, and the effect of rifampin pretreatment.

The metabolism of 14C-isonicotinyl hydrazide (INH) (50 mg/kg, po) was studied in male New Zealand White rabbits and the effect on INH metabolism of pretreating the rabbits for 7 days with rifampin (100 mg/kg po per day) was also studied. The 14C-labelled metabolites were separated and quantitated by TLC and the unlabelled hydrazino metabolites by GLC. Absorption and elimination of INH was rapid since the peak blood 14C level was attained by 1 hr and the T 1/2 of elimination was 2.67 +/- 0.36 hr. By 12 hr 68.5 +/- 4.1% of the dose was recovered in the urine. The major metabolite excreted in the urine was isonicotinic acid (INA) which accounted for 40.3 +/- 3.5% of the dose followed by acetylisoniazid (AcINH) at 15.8 +/- 1.2%. The relatively high proportion of INA excreted by the rabbit compared to the rat and human is attributed to a high level of amidase in the rabbit, and is suggested as a possible explanation for the rabbit's sensitivity to INH-induced hepatotoxicity. Rifampin pretreatment produced only one significant change in the parameters studied and that was a reduction in AcINH excreted in urine. It is suggested that this effect may be due to rifampin increasing hepatic amidase activity.