CYP2C8和CYP3A4酶主要参与人类胰岛素促分泌素的体外生物转化repaglinide。
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Bidstrup结核病,Bjornsdottir我Sidelmann UG,汤姆森女士,汉森KT次方
CYP2C8和CYP3A4酶主要参与人类胰岛素促分泌素的体外生物转化repaglinide。
Br中国新药杂志。2003年9月,56(3):305 - 14所示。
- PubMed ID
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12919179 (在PubMed]
- 文摘
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目的:确定主要人类细胞色素P450 (CYP)酶(s)负责repaglinide的人类体外生物转化。以前的实验发现CYP3A4作为主要负责repaglinide的体外代谢,但临床调查结果表明,多个酶可能参与repaglinide生物转化。方法:[14 c] -Repaglinide孵化与重组CYP和人类肝脏微粒体问题从个人捐赠者的抑制性抗体特定个人CYP酶。代谢物,用高效液相色谱法(HPLC)和在线放射化学检测,确定了液体色谱-分光光度法(质)和在线质耦合核磁共振波谱仪(LC-MS-NMR)。结果:发现CYP3A4和CYP2C8负责repaglinide转化为其两个主要代谢产物,M4(哌啶环上的羟基化带来的系统)和M1(一种芳香胺)。特定的抑制单克隆抗体对CYP3A4和CYP2C8显著地抑制M4的(> 71%)的形成,在高级别M1。在一个高级别小组从12个人捐赠者M4的形成和M1约160 - 880年不同pmol最低为1 mg-1蛋白质和100 - 1110年pmol最低为1 mg-1蛋白质,分别。生成的主要代谢物CYP2C8被发现M4。这种代谢物的生成率高与紫杉醇6 alpha-hydroxylation显著相关(r = 0.80;P = 0.0029)。 Two other minor metabolites were also detected. One of them was M1 and the other was repaglinide hydroxylated on the isopropyl moiety (M0-OH). The rate of formation of M4 in CYP2C8 Supersomes was 2.5 pmol min-1 pmol-1 CYP enzyme and only about 0.1 pmol min-1 pmol-1 CYP enzyme in CYP3A4 Supersomes. The major metabolite generated by CYP3A4 was M1. The rate of formation of this metabolite in HLM correlated significantly with testosterone 6beta-hydroxylation (rs = 0.90; P = 0.0002). Three other metabolites were identified, namely, M0-OH, M2 (a dicarboxylic acid formed by oxidative opening of the piperidine ring) and M5. The rate of M1 formation in CYP3A4 Supersomes was 1.6 pmol min-1 pmol-1 CYP enzyme but in CYP2C8 Supersomes it was only approximately 0.4 pmol min-1 pmol-1 CYP enzyme. CONCLUSIONS: The results confirm an important role for both CYP3A4 and CYP2C8 in the human in vitro biotransformation of repaglinide. This dual CYP biotransformation may have consequences for the clinical pharmacokinetics and drug-drug interactions involving repaglinide if one CYP pathway has sufficient capacity to compensate if the other is inhibited.
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药物 酶 类 生物 药理作用 行动 Repaglinide 细胞色素P450 2 c8 蛋白质 人类 未知的底物细节 Repaglinide 细胞色素P450 3 a4 蛋白质 人类 未知的底物细节 - 药物的相互作用Learn More" title="" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
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