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Fenretinide metabolism in humans and mice: utilizing pharmacological modulation of its metabolic pathway to increase systemic exposure
Author(s) -
Cooper Jason P,
Hwang Kyunghwa,
Singh Hardeep,
Wang Dong,
Reynolds C Patrick,
Curley Jr Robert W,
Williams Simon C,
Maurer Barry J,
Kang Min H
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01310.x
Subject(s) - ketoconazole , in vivo , cyp3a4 , fenretinide , pharmacokinetics , microsome , pharmacology , bioavailability , chemistry , metabolite , metabolism , cytochrome p450 , enzyme , biochemistry , biology , retinoid , antifungal , retinoic acid , microbiology and biotechnology , gene
BACKGROUND AND PURPOSE High plasma levels of fenretinide [N‐(4‐hydroxyphenyl)retinamide (4‐HPR)] were associated with improved outcome in a phase II clinical trial. Low bioavailability of 4‐HPR has been limiting its therapeutic applications. This study characterized metabolism of 4‐HPR in humans and mice, and to explore the effects of ketoconazole, an inhibitor of CYP3A4, as a modulator to increase 4‐HPR plasma levels in mice and to increase the low bioavailability of 4‐HPR. EXPERIMENTAL APPROACH 4‐HPR metabolites were identified by mass spectrometric analysis and levels of 4‐HPR and its metabolites [N‐(4‐methoxyphenyl)retinamide (4‐MPR) and 4‐oxo‐N‐(4‐hydroxyphenyl)retinamide (4‐oxo‐4‐HPR)] were quantified by high‐performance liquid chromatography (HPLC). Kinetic analysis of enzyme activities and the effects of enzyme inhibitors were performed in pooled human and pooled mouse liver microsomes, and in human cytochrome P450 (CYP) 3A4 isoenzyme microsomes. In vivo metabolism of 4‐HPR was inhibited in mice. KEY RESULTS Six 4‐HPR metabolites were identified in the plasma of patients and mice. 4‐HPR was oxidized to 4‐oxo‐4‐HPR, at least in part via human CYP3A4. The CYP3A4 inhibitor ketoconazole significantly reduced 4‐oxo‐4‐HPR formation in both human and mouse liver microsomes. In two strains of mice, co‐administration of ketoconazole with 4‐HPR in vivo significantly increased 4‐HPR plasma concentrations by > twofold over 4‐HPR alone and also increased 4‐oxo‐4‐HPR levels. CONCLUSIONS AND IMPLICATIONS Mice may serve as an in vivo model of human 4‐HPR pharmacokinetics. In vivo data suggest that the co‐administration of ketoconazole at normal clinical doses with 4‐HPR may increase systemic exposure to 4‐HPR in humans.