矛盾的作用,细胞色素P450 3 levo-alpha-acetylmethadol bioactivation和临床疗效:临床调查的重要性来验证体外药物代谢研究。

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Kharasch ED,惠廷顿D, Hoffer C, Krudys K,克雷格•K维克尼P, Sheffels P, Lalovic B

矛盾的作用,细胞色素P450 3 levo-alpha-acetylmethadol bioactivation和临床疗效:临床调查的重要性来验证体外药物代谢研究。

Pharmacokinet。2005; 44 (7): 731 - 51。doi: 10.2165 / 00003088-200544070-00005。

PubMed ID

15966756 (在PubMed

]

文摘

目的:Levo-alpha-acetylmethadol (levacetylmethadol LAAM)是一种长效阿片类受体激动剂用于防止阿片类戒断。LAAM经历顺序去norLAAM dinorLAAM,这是比LAAM longer-acting更有效。肝和肠微粒体酶体外去是催化主要是由细胞色素P450 (CYP) 3 a4;然而,LAAM CYP3A的角色性格在人体内是未知的。这次调查测试的假设CYP3A感应(或抑制)会增加(或减少)LAAM新陈代谢和bioactivation,因此,临床效果。它还相关LAAM性格的变化在酶抑制或诱导任何药理效应的变化。方法:健康志愿者(n = 13)完成了三方,随机,平衡的交叉研究。受试者接受口服LAAM(0.25毫克/公斤)后CYP3A感应(利福平(利福平)),抑制(troleandomycin)或(控制)。血浆和尿液LAAM, norLAAM dinorLAAM测定电喷射高性能液相色谱/质谱(HPLC / MS)。黑暗瞳孔直径变化的基线(减数分裂)LAAM效应的措施。 Results were analysed by noncompartmental methods and by a combined pharmacokinetic/pharmacodynamic model. RESULTS: Compared with controls, CYP3A induction (or inhibition) decreased (or increased) plasma LAAM concentrations and mean area under the plasma concentration-time curve from time zero to infinity (AUC(infinity) 199 +/- 91 [control] versus 11.3 +/- 4.0 [rifampicin] and 731 +/- 229 ng . h/mL [troleandomycin]; p < 0.05), and increased (or decreased) median formation clearances of norLAAM (1740 versus 14 100 and 302 mL/h/kg; p < 0.05) and dinorLAAM (636 versus 7840 and 173 mL/h/kg; p < 0.05). Surprisingly, however, CYP3A induction (or inhibition) decreased (or increased) mean plasma metabolite AUC from 0 to 96 hours (AUC(96)) [norLAAM + dinorLAAM] (859 +/- 241 versus 107 +/- 48 and 1185 +/- 179 ng . h/mL; p < 0.05) and clinical effects (mean miosis AUC(96) 128 +/- 40 versus 22.5 +/- 14.9 and 178 +/- 81 mm . h; p < 0.05). Clinical effects were best correlated with plasma norLAAM concentrations. CONCLUSION: CYP3A mediates human LAAM N-demethylation and bioactivation to norLAAM and dinorLAAM in vivo. Paradoxically, however, CYP3A induction decreased and inhibition increased LAAM active metabolite concentrations and clinical effects. This suggests a CYP3A-mediated metabolic pathway leading to inactive metabolites, which predominates over CYP3A-dependent bioactivation. These results highlight the need for clinical investigations to validate in vitro drug metabolism studies.

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
Levacetylmethadol	细胞色素P450 3 a4	蛋白质	人类	未知的	底物	细节