gastroprokinetic和止吐剂药物胃复安的底物和抑制剂细胞色素P450 2 d6。
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吴比伊·德斯塔Z,通用,Morocho,弗洛克哈特哒
gastroprokinetic和止吐剂药物胃复安的底物和抑制剂细胞色素P450 2 d6。
药物金属底座Dispos。2002年3月,30 (3):336 - 43。doi: 10.1124 / dmd.30.3.336。
- PubMed ID
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11854155 (在PubMed]
- 文摘
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胃复安是先前接受cisapride越来越规定条件,但其代谢酶学和药物相互作用知之甚少。使用人类的肝微粒体(高)和重组人细胞色素P450 (P450),我们确定了胃复安的主要路线,P450酶亚型氧化和参与。我们也记录了胃复安的抑制能力P450系统,使用isoform-specific CYP1A2的底物反应探针,2 c19 2 c9, 2 d6 2 e1, 3 a4。胃复安是主要N-dealkylated monodeethylmetoclopramide代谢物,迄今为止还没有在人类中描述。接着代谢物Michaelis-Menten动力学形成率(K (m), 68 + / - 16 microM;V (max), 183 + / - 57 pmol /分钟/毫克的蛋白质;n = 3高级别)。isoform-specific抑制剂的测试,1 microM奎尼丁的有效抑制剂胃复安(25 microM) monodeethylation(平均58.2%;范围,大约有38% (hl09 - 14 - 99)到78.7% (HL161)]与K (i)测试值高度可变的高级别(K (i),意味着美国南达科他州+ / -,2.7 + / - 2.8 microM;范围、0.15 microM HL66 2.4 microM hl09 - 14 - 99和5.7 microM HLD)。 Except troleandomycin, which inhibited metoclopramide metabolism in only one HLM (by approximately 23% in HL09-14-99), the effect of other inhibitors was minimal. Among the recombinant human P450 isoforms examined, monodeethylmetoclopramide was formed at the highest rate by CYP2D6 (V = 4.5 +/- 0.3 pmol/min/pmol of P450) and to a lesser extent by CYP1A2 (0.97 +/- 0.15 pmol/min/pmol of P450). The K(m) value derived (approximately 53 microM) was close to that from HLMs (68 microM). Metoclopramide is a potent inhibitor of CYP2D6 at therapeutically relevant concentrations (K(i) = 4.7 +/- 1.3 microM), with negligible effect on other isoforms tested. Further inhibition of CYP2D6 was observed when metoclopramide was preincubated with HLMs and NADPH-generating system before the substrate probe was added (maximum rate of inactivation, K(inact) = 0.02 min(-1), and the concentration required to achieve the half-maximal rate of inactivation, K'(i) = 0.96 microM), suggesting mechanism-based inhibition. Metoclopramide elimination is likely to be slowed in poor metabolizers of CYP2D6 or in patients taking inhibitors of this isoform, whereas metoclopramide itself could reduce the clearance of CYP2D6 substrate drugs.
beplay体育安全吗DrugBank数据引用了这篇文章
- 药物酶
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药物 酶 类 生物 药理作用 行动 胃复安 细胞色素P450 2 d6 蛋白质 人类 未知的底物抑制剂细节 - 药物反应
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反应 细节
