Affiliation:
1. Institut für Pharmakologie und Toxikologie, Abteilung Toxikologie, Eberhard-Karls-Universität Tübingen, Wilhelmstrasse 56, 72074 Tübingen, Germany
Abstract
Abstract
The opioid receptor antagonist naltrexone and the antiemetic 5-HT3 receptor antagonist dolasetron are ketonic drugs that are efficiently reduced to their corresponding alcohols in-vivo. These experiments aimed at characterizing the role in these reactions of individual oxidoreductases present in human liver cytosol. Aldo-keto reductases (AKRs) and carbonyl reductase (CR, EC 1.1.1.184) purified from human liver cytosol were incubated with varying substrate concentrations and 6β-naltrexol or reduced dolasetron were analysed by HPLC. AKR1C1, AKR1C2, and AKR1C4 were able to reduce both substrates. On the basis of kcat/Km values, AKR1C4 was nearly 1000-fold more efficient in reducing naltrexone than was AKR1C1, while AKR1C2 was of intermediate efficiency. Substrate inhibition was observed on incubating AKR1C2 or AKR1C4 with naltrexone. In contrast, dolasetron was also a substrate of CR. AKR1C1 and AKR1C4 were the most efficient enzymes in producing reduced dolasetron. We concluded that the efficient reduction of naltrexone by AKR1C4 probably causes the high 6β-naltrexol/naltrexone ratio in man. The rapid disappearance from human plasma of dolasetron given intravenously and its virtual absence after oral dosage are explained by its liability to reduction by several enzymes, including CR which shows widespread expression in human tissues.
Publisher
Oxford University Press (OUP)
Subject
Pharmaceutical Science,Pharmacology
Cited by
48 articles.
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