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OtherDRUG METABOLISM AND DISPOSITION

Human Liver CYP2B6-Catalyzed Hydroxylation of RP 73401

Jeffrey C. Stevens, Rebecca B. White, Shih Hsein Hsu and Michel Martinet
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1389-1395;
Jeffrey C. Stevens
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Rebecca B. White
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Shih Hsein Hsu
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Michel Martinet
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Abstract

RP 73401 is a potent inhibitor of cyclic nucleotide phosphodiesterase type IV. RP 73401 is metabolized by human liver microsomes almost exclusively by transhydroxylation of the cyclopentyl group to RPR 113406. Liquid chromatography/mass spectrometry/mass spectrometry analysis of plasma from patients given RP 73401 also revealed a molecular ion and fragmentation consistent with RPR 113406. Thus, the objective was to determine the oxidative enzyme(s) responsible for RP 73401 hydroxylation. Kinetic constants of RP 113406 formation ranged from 8 to 26 μM and 0.83 to 5.99 nmol/min/mg protein forKm and Vmax , respectively (n = 3). Enzyme activity varied 23-fold among 15 human liver microsome samples and correlated with CYP2A6-catalyzed coumarin hydroxylase (r2 = 0.85, P < .01) and CYP2B6-catalyzed 7-ethoxytrifluoromethylcoumarin O-deethylase (r2 = 0.82, P < .01) activities. Chemical inhibition studies showed a 63% decrease in RP 73401 hydroxylation by 500 μM orphenadrine. Coumarin (10 μM), however, did not inhibit RP 73401 hydroxylation. Also, anti-CYP2B1 IgG produced 85% inhibition of RP 73401 hydroxylation, but only a negligible decline in coumarin hydroxylase activity. Of the 10 expressed P450 forms studied, only CYP2B6 catalyzed RP 73401 hydroxylation. Finally, expressed CYP2B6 showed a high affinity (K m = 22.5 μM) for RP 73401 hydroxylation, similar to the human liver microsome studies.

Footnotes

  • Send reprint requests to: Jeffrey C. Stevens, Ph.D., Department of Drug Metabolism and Pharmacokinetics, Rhône-Poulenc Rorer, Mail Stop NW12, 500 Arcola Road, Collegeville, PA 19426.

  • Abbreviations:
    PDE
    phosphodiesterase
    7-EFC
    7-ethoxytrifluoromethylcoumarin
    7-HFC
    7-hydroxytrifluoromethyl coumarin
    G6PDH
    glucose-6-phosphate dehydrogenase
    TAO
    troleandomycin
    LC
    liquid chromatography
    MS
    mass spectrometry
    HPLC
    high-performance liquid chromatography
    HEPES
    4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
    FMO
    flavin monooxygenase
    • Received January 6, 1997.
    • Accepted May 19, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherDRUG METABOLISM AND DISPOSITION

Human Liver CYP2B6-Catalyzed Hydroxylation of RP 73401

Jeffrey C. Stevens, Rebecca B. White, Shih Hsein Hsu and Michel Martinet
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1389-1395;

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OtherDRUG METABOLISM AND DISPOSITION

Human Liver CYP2B6-Catalyzed Hydroxylation of RP 73401

Jeffrey C. Stevens, Rebecca B. White, Shih Hsein Hsu and Michel Martinet
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1389-1395;
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