The temporal variation in the pharmacokinetics of a single dose administration of isoniazid (INH) and its major metabolite, N-acetylisoniazid (AINH), was investigated at 0900 and 2100 in rats synchronized to a 12-hr light-dark cycle. INH and AINH were administered by the intraarterial and ip routes at a dose of 20 mg/kg, in order to determine the hepatic extraction ratio of both compounds. The mean AUC values of INH obtained after the intraarterial and ip injections of the drug were 42.6 and 8.4 micrograms.hr/ml at 0900 and 30.7 and 12.8 micrograms.hr/ml at 2100, respectively. Consequently, there were temporal variations (mean values at 0900 and 2100) in the clearance (491.6 and 665.3 ml/hr/kg), bioavailability (0.20 and 0.42), hepatic extraction ratio of INH (0.80 and 0.58), and apparent hepatic blood flow (9.7 and 18.6 ml/min). Also, the AUC of AINH was higher at 2100 when INH was injected intraarterially. Likewise, AINH had a lower t 1/2 and AUC values and a higher clearance at 2100, but the hepatic extraction ratio of AINH was 0.26 at 2100 compared with the value of 0.07 at 0900. No diurnal variations were present in the apparent volume of distribution of INH and AINH. In vitro experiments showed that the mean activity of the hepatic N-acetyltransferase was 135.3 nmol/mg at 2100, compared with 59.0 nmol/mg at 0900.(ABSTRACT TRUNCATED AT 250 WORDS)