Multiple dose pharmacokinetics of ketoconazole and their effects on antipyrine kinetics in man.

Ketoconazole 200 mg was given twice daily for five days to eight subjects. The serum pharmacokinetics were examined with the first dose on day 1 and with the ninth dose on day 5. The serum half life of ketoconazole was 74.8 +/- 13.9 min (mean +/- S.D.) on day 1, and 155.9 +/- 32.7 min on day 5. On day 1 the area under the serum concentration time curve was 626.9 +/- 230.1 mg/l.min, and 1441 +/- 897.3 mg/l.min on day 5. Antipyrine kinetics were determined before and after the course of ketoconazole. There was no significant change in the clearance and half life of antipyrine. Ketoconazole in the doses used in this study does not appear to alter hepatic microsomal enzyme activity in man. The increased ketoconazole half life and area under the serum concentration time curve on day 5 were in part caused by food. Other mechanisms for these changes such as saturation of a tissue compartment or a change in the elimination of ketoconazole during chronic dosing, may also be responsible.