Stereoselective metabolism of bisoprolol enantiomers in dogs and humans.
To clarify the mechanism of the species difference in the metabolism of bisoprolol enantiomers, in vitro metabolic studies were performed using dog liver microsomes and human cytochrome P450 (CYP) isoforms. The O-deisopropylation of bisoprolol enantiomers showed biphasic kinetics in dog liver microsomes. The intrinsic clearance (Vmax/Km) for O-deisopropylation of R(+)-bisoprolol was higher than S(-)-isomer in both high-affinity and low-affinity components. The R/S ratio of the intrinsic clearance in high- and low-affinity components was 1.34 and 1.65, respectively. The inhibition studies in dog liver microsomes using CYP isoform-selective inhibitors indicated that the O-deisopropylation of both bisoprolol enantiomers was mediated via the CYP2D and CYP3A subfamily, and suggested that high-affinity oxidation was dependent on CYP2D. The kinds of CYP subfamilies in dogs, which contribute to the metabolism of bisoprolol enantiomers, were the same as those in humans. The intrinsic clearance for O-deisopropylation of R(+)bisoprolol by human recombinant CYP2D6 was also different from that of S(-)-enantiomers (R/S:1.50). However, unlike the dog microsomes, the intrinsic clearance by the human recombinant CYP3A4 did not show a stereoselective difference. Therefore, the species difference in the R/S ratio of metabolic clearance for the oxidation of bisoprolol enantiomers (dog > human) is mainly due to the species difference in the stereoselectivity of one of the cytochrome P450 subfamilies (CYP3A).
Horikiri
Y
Y
Pharmaceutics Research Laboratory, Tanabe Seiyaku Co., Ltd, Osaka, Japan. horikiri@tanabe.co.jp
Suzuki
T
T
Mizobe
M
M
D000319:Adrenergic beta-Antagonists / Q000378:metabolism* / Q000493:pharmacokinetics*; D000818:Animals; D017298:Bisoprolol / Q000378:metabolism* / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D013045:Species Specificity; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D017298:Bisoprolol