Takekuma Yoh, Takenaka Toru, Yamazaki Koujiro, Ueno Kazuyuki, Sugawara Mitsuru
Laboratory of Pharmcotherapeutic Information, Department of Biopharmaceutical Sciences and Pharmacy, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo, Japan.
Biol Pharm Bull. 2007 Nov;30(11):2146-53. doi: 10.1248/bpb.30.2146.
Carvedilol, an alpha- and beta-adrenergic blocking drug, is mainly metabolized by CYP2D6, UGT1A1, UGT2B4 and UGT2B7. This drug is administered orally as a racemic mixture of R(+)- and S(-)-enantiomers. It has been reported that CYP2D6 prefers metabolizing S-carvedilol to R-carvedilol stereoselectively. On the other hand, stereoselective metabolism of carvedilol by UGTs is still unclear. Moreover, we have reported that patients with chronic heart failure who had polymorphism in CYP2D6, UGT1A1 and/or UGT2B7 had lower metabolic activity and oral clearance than did patients with no polymorphism. The aim of this study was to clarify stereoselective metabolism of carvedilol by UGT1A1 and UGT2B7 and to determine by using a recombinant enzyme-introduced mutation whether genetic mutation in UGT1A1 and UGT2B7 causes reduction in metabolic activity for carvedilol. A glucuronidation assay using human liver microsomes and recombinant UGT1A1 and UGT2B7 expressed in HeLa cells demonstrated that UGT1A1 prefers metabolizing R-carvedilol to S-carvedilol. On the other hand, UGT2B7 prefers metabolizing S-carvedilol to R-carvedilol. Moreover, G71R mutation of UGT1A1 reduced both affinity and capacity but did not affect stereoselective metabolism. On the other hand, both A71S and H268Y mutations of UGT2B7 reduced capacity but did not affect affinity and, as a result, the efficiency of metabolism was remarkably reduced. However, as in the case of UGT1A1, neither of the mutations affected stereoselective metabolism.
卡维地洛是一种α和β肾上腺素能阻断药物，主要通过CYP2D6、UGT1A1、UGT2B4和UGT2B7进行代谢。该药物以R(+)-和S(-)-对映体的外消旋混合物形式口服给药。据报道，CYP2D6对S-卡维地洛的代谢比对R-卡维地洛具有立体选择性。另一方面，UGTs对卡维地洛的立体选择性代谢仍不清楚。此外，我们曾报道，CYP2D6、UGT1A1和/或UGT2B7存在多态性的慢性心力衰竭患者，其代谢活性和口服清除率低于无多态性的患者。本研究的目的是阐明UGT1A1和UGT2B7对卡维地洛的立体选择性代谢，并通过使用重组酶引入突变来确定UGT1A1和UGT2B7中的基因突变是否会导致卡维地洛代谢活性降低。使用人肝微粒体以及在HeLa细胞中表达的重组UGT1A1和UGT2B7进行的葡萄糖醛酸化试验表明，UGT1A1对R-卡维地洛的代谢比对S-卡维地洛更具偏好性。另一方面，UGT2B7对S-卡维地洛的代谢比对R-卡维地洛更具偏好性。此外，UGT1A1的G71R突变降低了亲和力和代谢能力，但不影响立体选择性代谢。另一方面，UGT2B7的A71S和H268Y突变均降低了代谢能力，但不影响亲和力，结果代谢效率显著降低。然而，与UGT1A1的情况一样，这两种突变均不影响立体选择性代谢。
