ITRACONAZOLE AND HYDROXYITRACONAZOLE SERUM CONCENTRATIONS ARE REDUCEDMORE THAN TENFOLD BY PHENYTOIN

Objective: To study the disposition of single doses of phenytoin and i traconazole when administered alone and after chronic treatment with t he other drug. Methods: Healthy male volunteers were randomized to two groups and studied in parallel. In group 1, a single 200 mg oral dose of itraconazole was administered on two occasions (alone and after 15 days of 300 mg oral phenytoin once daily). Subjects in group 2 were g iven a single 300 mg oral dose of phenytoin before and after 15 days o f itraconazole (200 mg once daily). Blood was collected for 96 hours a fter each single dose of phenytoin or itraconazole. Serum was assayed for itraconazole and hydroxyitraconazole concentration by HPLC and for phenytoin concentration by fluorescence polarization immunoassay. Res ults: Phenytoin decreased the area under the concentration-time curve (AUG) of itraconazole by more than 90%, from 3203 to 224 ng . hr/ml, a ccompanied by a decrease in half-life from 22.3 to 3.8 hours. Similar changes were observed for hydroxyitraconazole AUC (decreased from 6224 to 315 ng hr/ml) and half-life (11.3 versus 2.9 hours), Itraconazole increased the AUC of phenytoin (10.3%; p < 0.05), with no change in an y other pharmacokinetic parameter. Conclusions: The striking decrease in itraconazole concentrations with phenytoin is due to induction of m etabolism combined with a reduction in the degree of saturable metabol ism normally exhibited by itraconazole at this dose. The magnitude of interaction likely accounts for reports of therapeutic failures in pat ients with fungal infections who are receiving both itraconazole and p henytoin.