THE EFFECT OF PHENYTOIN ON THE PHARMACOKINETICS OF TIRILAZAD MESYLATE IN HEALTHY MALE-VOLUNTEERS

The pharmacokinetic interaction between phenytoin and tirilazad was studied in 12 healthy men who received 200 mg phenytoin orally every 8 hours for 11 doses and 100 mg for the remaining 5 doses in one period of a two-way crossover study. In both periods, 1.5 mg/kg tirilazad mesylate was administered (as 10-minute intravenous infusions) every 6 hours for 21 doses (5 days). Plasma tirilazad mesylate and U-89678 (an active metabolite) were quantified by HPLC. After dose 21, area under the plasma concentration-time curve [AUC(0-6)] for tirilazad mesylate was significantly lower (p = 0.0061) after phenytoin treatment (3029 +/- 982 ng . hr/ml) than after tirilazad mesylate alone (4647 +/- 1562 ng . hr/ml). AUC(0-6) for U-89,678 after dose 21 was reduced from 1485 +/- 1173 ng . hr/ml after tirilazad mesylate alone to 195 +/- 223 ng . hr/ml after phenytoin coadministration. U-89678 normally accumulates during multiple dosing, but mean U-89678 trough concentrations decreased after 24 hours during tirilazad and phenytoin coadministration. No clinically significant interactions of tirilazad mesylate and phenytoin for medical events, vital signs, or laboratory parameters were identified. These results suggest that phenytoin rapidly induces tirilazad mesylate metabolism; it may also induce the metabolism of U-89678 or shunt tirilazad mesylate metabolism through other pathways.