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Vol. 282, Issue 3, 1389-1395, 1997

Human Liver CYP2B6-Catalyzed Hydroxylation of RP 73401

Jeffrey C. Stevens, Rebecca B. White, Shih Hsein Hsu and Michel Martinet

Department of Drug Metabolism and Pharmacokinetics, Rhône-Poulenc Rorer, Collegeville, Pennsylvania (J.C.S., R.B.W., S.H.H.) and Centre de Recherche de Vitry-Alfontville, 94403 Vitry Sur Seine Cedex, France (M.M.)

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 for Km 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 (Km = 22.5 µM) for RP 73401 hydroxylation, similar to the human liver microsome studies.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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