Carbonyl reduction of naltrexone and dolasetron by oxidoreductases isolated from human liver cytosol.

摘要: The opioid receptor antagonist naltrexone and the antiemetic 5-HT(3) dolasetron are ketonic drugs that efficiently reduced to their corresponding alcohols in-vivo. These experiments aimed at characterizing role in these reactions of individual oxidoreductases present human liver cytosol. Aldo-keto reductases (AKRs) carbonyl reductase (CR, EC 1.1.1.184) purified from cytosol were incubated with varying substrate concentrations 6beta-naltrexol or analysed by HPLC. AKR1C1, AKR1C2, AKR1C4 able reduce both substrates. On basis k(cat)/K(m) values, was nearly 1000-fold more efficient reducing than while AKR1C2 intermediate efficiency. Substrate inhibition observed on incubating naltrexone. In contrast, also a CR. AKR1C1 most enzymes producing dolasetron. We concluded reduction probably causes high 6beta-naltrexol/naltrexone ratio man. rapid disappearance plasma given intravenously its virtual absence after oral dosage explained liability several enzymes, including CR which shows widespread expression tissues.