Stereoselective metabolism of verapamil and four other chiral drugs by cDNA expressed CYP450's.

摘要

Stereoselectivity in pharmacokinetics, pharmacodynamics and drug metabolism has critical impact in the drug development. We systematically studied the stereoselectivity in the in vitro metabolism of verapamil, propranolol, warfarin, metoprolol, and 4-[benzyl(tert-butyl)amino]-2-phenyl-2-pyridin-2-ylbutanamide (PPY) enantiomers, as catalyzed by different cDNA-expressed cytochrome P450 isozymes.; In our studies, we reported verapamil stereo selectivity by human CYP3A4, CYP3A5, CYP3A7, CYP2C8, CYP2C19, CYP2C9, CYP2D6, and CYP2B6, propranolol stereoselectivity by human CYP1A1, CYP1A2, CYP2D6, CYP2C19, and CYP1Bl, warfarin stereoselectivity by human CYP1A1, CYP1A2, CYP2C9, and CYP2C19, metoprolol stereo selectivity by human CYP2D6, PPY stereoselectivity by human CYP3A4, CYP3A5, CYP2C8, CYP2C18, and CYP2C19.; Atypical kinetics was observed in verapamil, propranolol, and PPY studies. The kinetic metabolism of verapamil enantiomers by different cDNA-expressed isozymes displayed atypical kinetic profiles: substrate inhibition and biphasic kinetics with CYP3A4, CYP3A5, substrate inhibition with CYP3A7, CYP2C8, CYP2D6, autoactivation with CYP2C9, CYP2C19, and CYP2B6. Midazolam, testosterone, and nifedipine inhibition data with CYP3A4, CYP3A5, and CYP3A12 displayed differential inhibition, inhibitor-dependence, metabolite-dependence, and enantiomer-dependence. Propranolol enantiomer metabolism by CYP1A2 and CYP2C19 displayed biphasic kinetic profile. (+)-PPY and (−)-PPY metabolism by cDNA-expressed CYP3A4 and CYP3A5 displayed biphasic kinetic profile. Finally, a two binding-site model was proposed to explain the atypical kinetics and inhibition data observed.