INHIBITION OF ALL-TRANS-RETINOIC ACID METABOLISM BY FLUCONAZOLE IN-VITRO AND IN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA

All-trans-retinoic acid induces acute promyelocytic leukemia cell diff erentiation in vitro, and it produces greater than 90% complete remiss ions in patients with acute promyelocytic leukemia. Despite the high r esponse rate, the majority of patients relapse with continued trans-re tinoic acid therapy, and disease progression has been observed to be a ccompanied by an increase in the metabolism of trans-retinoic acid in the patients. In this study, the pharmacokinetic disposition of bans-r etinoic acid was determined by HPLC in patients with acute promyelocyt ic leukemia before and after concurrent therapy with the triazole anti mycotic agent fluconazole. Treatment with trans-retinoic acid for 1 we ek reduced the area under the plasma trans-retinoic acid concentration vs time curve in one patient by 67%, from 277 to 91 ng/mL/hr. Trans-r etinoic acid pharmacokinetics were repeated after the second dose of f luconazole, administered 1 hour prior to the retinoid, and the AUC was found to be 401 ng/ml/hr, a greater than 4-fold increase from the pre -fluconazole level. A similar, though more modest, effect of fluconazo le was seen in a second acute promyelocytic leukemia patient. The effe ct of fluconazole on trans-retinoic acid metabolism was examined in vi tro using isolated human hepatic microsomes. Fluconazole inhibited the NADPH-dependent cytochrome P450-mediated catabolism of trans-retinoic acid in a concentration-dependent manner. Although fluconazole was ap proximately one-half as potent an inhibitor when compared with ketocon azole, a related antifungal drug, 60-90% inhibition was observed at th e concentrations of fluconazole measured in the acute promyelocytic le ukemia patients. Neither fluconazole nor ketoconazole inhibited lipid hydroperoxide-mediated metabolism of Irans-retinoic acid. Since flucon azole is a well-tolerated agent frequently administered to leukemia pa tients, its use in combination with trans-retinoic acid merits further consideration.