title: Inhibition of all-trans-retinoic acid metabolism by fluconazole in vitro and in patients with acute promyelocytic leukemia.
abstract: All-trans-retinoic acid induces acute promyelocytic leukemia cell differentiation in vitro, and it produces greater than 90% complete remissions in patients with acute promyelocytic leukemia. Despite the high response rate, the majority of patients relapse with continued trans-retinoic acid therapy, and disease progression has been observed to be accompanied by an increase in the metabolism of trans-retinoic acid in the patients. In this study, the pharmacokinetic disposition of trans-retinoic acid was determined by HPLC in patients with acute promyelocytic leukemia before and after concurrent therapy with the triazole antimycotic agent fluconazole. Treatment with trans-retinoic acid for 1 week 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-retinoic acid pharmacokinetics were repeated after the second dose of fluconazole, 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 fluconazole was seen in a second acute promyelocytic leukemia patient. The effect of fluconazole on trans-retinoic acid metabolism was examined in vitro 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 approximately one-half as potent an inhibitor when compared with ketoconazole, a related antifungal drug, 60-90% inhibition was observed at the concentrations of fluconazole measured in the acute promyelocytic leukemia patients. Neither fluconazole nor ketoconazole inhibited lipid hydroperoxide-mediated metabolism of trans-retinoic acid. Since fluconazole is a well-tolerated agent frequently administered to leukemia patients, its use in combination with trans-retinoic acid merits further consideration.
authors.affiliation: Department of Oncology, Albert Einstein College of Medicine, Bronx, NY 10467, USA.
authors.forename: E L
authors.initials: EL
authors.lastname: Schwartz
authors.forename: S
authors.initials: S
authors.lastname: Hallam
authors.forename: R E
authors.initials: RE
authors.lastname: Gallagher
authors.forename: P H
authors.initials: PH
authors.lastname: Wiernik
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D015473:Leukemia, Promyelocytic, Acute / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D014212:Tretinoin / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000935:Antifungal Agents; D014212:Tretinoin; D015725:Fluconazole