Elsevier

Biochemical Pharmacology

Volume 50, Issue 7, 28 September 1995, Pages 923-928
Biochemical Pharmacology

Research paper
Inhibition of all-trans-retinoic acid metabolism by fluconazole in vitro and in patients with acute promyelocytic leukemia

https://doi.org/10.1016/0006-2952(95)00213-JGet rights and content

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.

References (30)

  • PD Fiorella et al.

    Microsomal retinoic acid metabolism. Effects of cellular retinoic acid-binding protein (type I) and C18-hydroxylation as an initial step

    J Biol Chem

    (1994)
  • JRF Muindi et al.

    Clinical pharmacology of oral all-trans-retinoic acid in patients with acute promyelocytic leukemia

    Cancer Res

    (1992)
  • MA Smith et al.

    Phase I and pharmacokinetic evaluation of all-transretinoic acid in pediatric patients with cancer

    J Clin Oncol

    (1992)
  • JR Rigas et al.

    Constitutive variability in the pharmacokinetics of the natural retinoid, all-trans-retinoic acid, and its modulation by ketoconazole

    J Natl Cancer Inst

    (1993)
  • JB Williams et al.

    Metabolism of retinoic acid and retinol during differentiation of F9 embryonal carcinoma cells

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    The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

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