遗传决定因素的人类肝脏微粒体alfentanil新陈代谢和细胞色素P450 3 a5的角色。

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克利TM Sheffels P Thummel KE, Kharasch ED

遗传决定因素的人类肝脏微粒体alfentanil新陈代谢和细胞色素P450 3 a5的角色。

麻醉学。2005年3月,102 (3):550 - 6。

PubMed ID

15731592 (在PubMed

]

文摘

背景:有相当大的无法解释的个人间的间隙变化alfentanil。由细胞色素P4503A4 Alfentanil经历广泛的代谢(CYP3A4)。CYP3A5在结构上类似于CYP3A4和最CYP3A4代谢基质,但以多态方式表达。肝脏与CYP3A5 * 1等位基因含有大量的原生CYP3A5蛋白质比肝脏变异CYP3A5 * 3等位基因纯合子。这次调查测试的假设alfentanil是CYP3A5衬底和CYP3A5药物遗传变异性影响人类肝脏alfentanil新陈代谢。方法:Alfentanil新陈代谢noralfentanil和N-phenylpropionamide决心从两组人类肝脏微粒体,对CYP3A4和CYP3A5蛋白质含量特征:低CYP3A5 (CYP3A总量的2.0 - -5.2%,n = 10)和高CYP3A5 (46 - CYP3A总量的76%,n = 10)。两组意味着CYP3A4的内容是一样的。CYP3A抑制剂troleandomycin和酮康唑的影响,后者更有效对CYP3A4 alfentanil代谢也决定。结果:在低和高CYP3A5肝脏,分别noralfentanil形成是77 + / - 31和255 + / - 170 pmol。分钟。 mg, N-phenylpropionamide formation was 8.0 +/- 3.1 versus 20.5 +/- 14.0 pmol . min . mg, and the metabolite ratio was 9.5 +/- 0.4 versus 12.7 +/- 1.4 (P < 0.05 for all). There was a poor correlation between alfentanil metabolism and CYP3A4 content but an excellent correlation when CYP3A5 (i.e., total CYP3A content) was considered (r = 0.81, P < 0.0001). Troleandomycin inhibited alfentanil metabolism similarly in the low and high CYP3A5 livers; ketoconazole inhibition was less in the high CYP3A5 livers. CONCLUSION: In microsomes from human livers expressing the CYP3A5*1 allele and containing higher amounts of CYP3A5 protein, compared with those with the CYP3A5*3 allele and little CYP3A5, there was greater alfentanil metabolism, metabolite ratios more closely resembled those for expressed CYP3A5, and inhibitors with differing CYP3A4 and CYP3A5 selectivities had effects resembling those for expressed CYP3A5. Therefore, alfentanil is metabolized by human liver microsomal CYP3A5 in addition to CYP3A4, and pharmacogenetic variability in CYP3A5 expression significantly influences human liver alfentanil metabolism in vitro. Further investigation is warranted to assess whether the CYP3A5 polymorphism is a factor in the interindividual variability of alfentanil metabolism and clearance in vivo.

DrugBank数据引用了这篇文章

药物酶

药物	酶	类	生物	药理作用	行动
Alfentanil	细胞色素P450 3 a4	蛋白质	人类	未知的	底物	细节
Alfentanil	细胞色素P450 3 a5	蛋白质	人类	未知的	底物	细节