The contributions of cytochromes P450 3A4 and 3A5 to the metabolism of the phosphodiesterase type 5 inhibitors sildenafil, udenafil, and vardenafil
The contributions of cytochromes P450 3A4 and 3A5 to the metabolism of the phosphodiesterase type 5 inhibitors sildenafil, udenafil, and vardenafil
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DOI：
10.1124/dmd.107.020099
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发表时间：
2008-06-01
影响因子：
3.9
通讯作者：
Liu, Kwang-Hyeon
中科院分区：
文献类型：
--
作者：
Ku, Hei-Young;Ahn, Hee-Jeong;Liu, Kwang-Hyeon
基因多态的细胞色素P3A5在细胞色素P3A底物代谢中的作用尚不清楚。我们研究了CYP3A4和CYP3A5亚型在磷酸二酯酶5类抑制剂(PDE5I)西地那非、乌地那非和伐地那非代谢中的作用。用重组细胞色素P3A酶和15种具有预定基因型人肝微体(HLM)标本进行了西地那非N-脱甲基化、乌地那非N-脱烷基化和伐地那非N-脱乙基化的体外孵育研究。重组细胞色素P3A4和细胞色素P3A5均产生西地那非、乌地那非和伐地那非的N-脱烷基代谢物。RCYP3A5异构体对伐地那非N-脱乙基化的催化效率(CI-int=V-max/表观K-m)约为rCYP3A4的3.2倍，而西地那非和乌地那非的本征清除率与rCYP3A4相似。CYP3A5*3杂合子(n=9)的代谢产物形成活性高于纯合子(n=6)。这些发现表明，CYP3A5和CYP3A4在PDE5I的代谢中起着重要作用。CYP3A5的遗传多态可能导致PDE5I的个体间差异，特别是伐地那非。需要进一步的体内研究来证实CYP3A5基因对PDE5I药代动力学的影响。
The role of the genetically polymorphic CYP3A5 in the metabolism of CYP3A substrates is unclear. We investigated the contributions of the CYP3A4 and CYP3A5 isoforms to the metabolism of the phosphodiesterase type 5 inhibitors (PDE5Is) sildenafil, udenafill, and vardenafil. In vitro incubation studies of sildenafil N-demethylation, udenafil N-dealkylation, and vardenafil N-deethylation were conducted using recombinant CYP3A enzymes and 15 human liver microsome (HLM) preparations with predetermined CYP3A5 genotypes. Recombinant CYP3A4 and CYP3A5 both produced N-desalkyl metabolites of sildenafil, udenafil, and vardenafil. The catalytic efficiency (Cl-int = V-max/apparent K-m) of the rCYP3A5 isoform for vardenafil N-deethylation was about 3.2-fold that of rCYP3A4, whereas the intrinsic clearance rates for N-dealkylation of both sildenafil and udenafil were similar between rCYP3A5 and rCYP3A4. The metabolite formation activity was higher in HLMs heterozygous for the CYP3A5*3 allele (n = 9) than in HLMs homozygous for CYP3A5*3 (n = 6). These findings suggest that CYP3A5 and CYP3A4 play a significant role in the metabolism of PDE5Is. The genetic polymorphism of CYP3A5 may contribute to interindividual variability in the disposition of PDE5Is, especially vardenafil. Further in vivo studies are needed to confirm the effects of CYP3A5 genotypes on the pharmacokinetics of PDE5Is.