Skarydova Lucie, Tomanova Radana, Havlikova Lucie, Stambergova Hana, Solich Petr, Wsol Vladimir
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague.
Drug Metab Pharmacokinet. 2014;29(2):177-84. doi: 10.2133/dmpk.dmpk-13-rg-051. Epub 2013 Oct 1.
Bupropion is widely used as an antidepressant drug and also as a smoking cessation aid. In humans, this drug is extensively metabolized to form several metabolites. Oxidised hydroxybupropion and two reduced metabolites, threohydrobupropion and erythrohydrobupropion, are major metabolites. All of these metabolites are considered to be active. Although the oxidative metabolic pathway and the central role of CYP2B6 are known, the enzymes that participate in the reduction have not been identified to date. The aim of this study was to confirm the role of human liver subcellular fractions in the metabolism of bupropion and elucidate the contribution of particular carbonyl-reducing enzymes. An HPLC method for the determination of bupropion metabolites was utilised. Bupropion is reduced to threohydrobupropion and less to erythrohydrobupropion in human liver cytosol, microsomes and also mitochondria. Surprisingly, intrinsic clearance for formation of both metabolites is the highest in mitochondrial fraction. Moreover this study provides the first direct evidence that 11β-hydroxysteroid dehydrogenase 1, AKR1C1, AKR1C2, AKR1C3 and CBR1 participate in the reducing biotransformation of bupropion in vitro. The enzyme kinetics of all of these reductases was investigated and kinetic parameters were calculated.
安非他酮被广泛用作抗抑郁药物，也用作戒烟辅助药物。在人体内，这种药物会广泛代谢形成多种代谢产物。氧化羟基安非他酮以及两种还原代谢产物，即苏式羟基安非他酮和赤式羟基安非他酮，是主要的代谢产物。所有这些代谢产物都被认为具有活性。尽管氧化代谢途径以及细胞色素P450 2B6（CYP2B6）的核心作用已为人所知，但迄今为止，参与还原反应的酶尚未得到鉴定。本研究的目的是确认人肝脏亚细胞组分在安非他酮代谢中的作用，并阐明特定羰基还原酶的贡献。采用了一种高效液相色谱法（HPLC）来测定安非他酮的代谢产物。在人肝脏胞质溶胶、微粒体以及线粒体中，安非他酮被还原为苏式羟基安非他酮，还原为赤式羟基安非他酮的量较少。令人惊讶的是，两种代谢产物形成的内在清除率在线粒体组分中最高。此外，本研究首次直接证明11β - 羟基类固醇脱氢酶1、醛酮还原酶1C1（AKR1C1）、醛酮还原酶1C2（AKR1C2）、醛酮还原酶1C3（AKR1C3）和羰基还原酶1（CBR1）在体外参与安非他酮的还原生物转化。研究了所有这些还原酶的酶动力学，并计算了动力学参数。
