title: Evaluation of 24 CYP2D6 Variants on the Metabolism of Nebivolol In Vitro.
abstract: CYP2D6 is an important cytochrome P450 (P450) enzyme that metabolizes approximately 25% of therapeutic drugs. Its genetic polymorphisms may significantly influence the pharmacokinetics and pharmacodynamics of clinically used drugs. Studying the effects of CYP2D6 on drug metabolism can help reduce adverse drug reactions and therapeutic failure to some extent. This study aimed to investigate the role of CYP2D6 in nebivolol metabolism by evaluating the effect of 24 CYP2D6 variants on the metabolism of nebivolol in vitro. CYP2D6 variants expressed by insect cell systems were incubated with 0.1-80 μM nebivolol for 30 minutes at 37°C and the reaction was terminated by cooling to -80°C immediately. An ultra-performance liquid chromatography-tandem mass spectrometry system was used to analyze nebivolol and its metabolite 4-hydroxy nebivolol. Compared with CYP2D6.1, the intrinsic clearance values of most variants were significantly altered, and most of these variants exhibited either reduced Vmaxand/or increased Kmvalues. Variant R440C showed much higher intrinsic clearance than the wild type (219.08%). Five variants (CYP2D6.88, CYP2D6.89, R344Q, V342M, and D336N) exhibited no difference from the wild type. CYP2D6.92 and CYP2D6.96 displayed weak or no activity, whereas the intrinsic clearance values of the remaining 16 variants were significantly reduced to various degrees (ranging from 4.07% to 71%). As the first report of 24 CYP2D6 alleles for nebivolol metabolism, these results are valuable to interpreting in vivo studies and may also serve as a reference for rational clinical administration.
authors.affiliation: School of Pharmacy (X.H., T.L., L.Y., Q.Z., Y.L., G.H.) and First Affiliated Hospital (R.X.), Wenzhou Medical University, Wenzhou, Zhejiang, China; and Key Laboratory of Geriatrics, Beijing Hospital, Beijing, China (D.D., J.C.).
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Hu
authors.affiliation: School of Pharmacy (X.H., T.L., L.Y., Q.Z., Y.L., G.H.) and First Affiliated Hospital (R.X.), Wenzhou Medical University, Wenzhou, Zhejiang, China; and Key Laboratory of Geriatrics, Beijing Hospital, Beijing, China (D.D., J.C.).
authors.forename: Tian
authors.initials: T
authors.lastname: Lan
authors.affiliation: School of Pharmacy (X.H., T.L., L.Y., Q.Z., Y.L., G.H.) and First Affiliated Hospital (R.X.), Wenzhou Medical University, Wenzhou, Zhejiang, China; and Key Laboratory of Geriatrics, Beijing Hospital, Beijing, China (D.D., J.C.).
authors.forename: Dapeng
authors.initials: D
authors.lastname: Dai
authors.affiliation: School of Pharmacy (X.H., T.L., L.Y., Q.Z., Y.L., G.H.) and First Affiliated Hospital (R.X.), Wenzhou Medical University, Wenzhou, Zhejiang, China; and Key Laboratory of Geriatrics, Beijing Hospital, Beijing, China (D.D., J.C.).
authors.forename: Ren-Ai
authors.initials: RA
authors.lastname: Xu
authors.affiliation: School of Pharmacy (X.H., T.L., L.Y., Q.Z., Y.L., G.H.) and First Affiliated Hospital (R.X.), Wenzhou Medical University, Wenzhou, Zhejiang, China; and Key Laboratory of Geriatrics, Beijing Hospital, Beijing, China (D.D., J.C.).
authors.forename: Lingjing
authors.initials: L
authors.lastname: Yuan
authors.affiliation: School of Pharmacy (X.H., T.L., L.Y., Q.Z., Y.L., G.H.) and First Affiliated Hospital (R.X.), Wenzhou Medical University, Wenzhou, Zhejiang, China; and Key Laboratory of Geriatrics, Beijing Hospital, Beijing, China (D.D., J.C.).
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: School of Pharmacy (X.H., T.L., L.Y., Q.Z., Y.L., G.H.) and First Affiliated Hospital (R.X.), Wenzhou Medical University, Wenzhou, Zhejiang, China; and Key Laboratory of Geriatrics, Beijing Hospital, Beijing, China (D.D., J.C.).
authors.forename: Yunxuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Pharmacy (X.H., T.L., L.Y., Q.Z., Y.L., G.H.) and First Affiliated Hospital (R.X.), Wenzhou Medical University, Wenzhou, Zhejiang, China; and Key Laboratory of Geriatrics, Beijing Hospital, Beijing, China (D.D., J.C.).
authors.forename: Jianping
authors.initials: J
authors.lastname: Cai
authors.affiliation: School of Pharmacy (X.H., T.L., L.Y., Q.Z., Y.L., G.H.) and First Affiliated Hospital (R.X.), Wenzhou Medical University, Wenzhou, Zhejiang, China; and Key Laboratory of Geriatrics, Beijing Hospital, Beijing, China (D.D., J.C.) hgx@wmu.edu.cn.
authors.forename: Guoxin
authors.initials: G
authors.lastname: Hu
mesh_terms: D000483:Alleles; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007700:Kinetics; D008861:Microsomes / Q000378:metabolism; D000068577:Nebivolol / Q000378:metabolism*
chemical_list: D000068577:Nebivolol; D019389:Cytochrome P-450 CYP2D6