THE EFFECT OF PHENYTOIN ON THE PHARMACOKINETICS OF TIRILAZAD MESYLATEIN HEALTHY MALE-VOLUNTEERS

The pharmacokinetic interaction between phenytoin and tirilazad was st udied in 12 healthy men who received 200 mg phenytoin orally every 8 h ours for 11 doses and 100 mg for the remaining 5 doses in one period o f a two-way crossover study. In both periods, 1.5 mg/kg tirilazad mesy late was administered (as 10-minute intravenous infusions) every 6 hou rs for 21 doses (5 days). Plasma tirilazad mesylate and U-89678 (an ac tive metabolite) were quantified by HPLC. After dose 21, area under th e plasma concentration-time curve [AUC(0-6)] for tirilazad mesylate wa s 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 d uring multiple dosing, but mean U-89678 trough concentrations decrease d after 24 hours during tirilazad and phenytoin coadministration. No c linically significant interactions of tirilazad mesylate and phenytoin for medical events, vital signs, or laboratory parameters were identi fied. These results suggest that phenytoin rapidly induces tirilazad m esylate metabolism; it may also induce the metabolism of U-89678 or sh unt tirilazad mesylate metabolism through other pathways.