In vitro approach to elucidate the relevance of carboxylesterase 2 and N-acetyltransferase 2 to flupirtine-induced liver injury

Biochemical Pharmacology
Keigo KonishiMiki Nakajima

Abstract

The use of flupirtine, an analgesic, has been restricted in European countries because it causes liver injury in rare cases. Flupirtine is primarily metabolized to D-13223, an acetylamino form. In the process of D-13223 formation, it has been hypothesized that a reactive metabolite is formed which may be involved in flupirtine hepatotoxicity. The purpose of this study was to identify the potential reactive metabolite and the responsible enzymes in the human liver to get a clue to the mechanism of hepatotoxicity. Using recombinant enzymes, we found that D-13223 was formed from flupirtine via hydrolysis by carboxylesterase 2 (CES2) and subsequent acetylation by N-acetyltransferase (NAT) 2. A conjugate of N-acetyl-l-cysteine (NAC), a nucleophile, was detected by incubation of flupirtine with CES2, and the conjugate formation in human liver microsomes was inhibited by CES2 inhibitors, indicating that a reactive metabolite, which may be a quinone diimine, was produced in the process of CES2-mediated hydrolysis of flupirtine. The formation of the NAC conjugate in liver S9 samples from NAT2 slow acetylators was significantly higher than that from NAT2 rapid/intermediate acetylators, indicating that NAT2 could function as a detoxificat...Continue Reading

Citations

Nov 8, 2018·Organic & Biomolecular Chemistry·Christian BockAndreas Link
Jul 9, 2020·Experimental and Clinical Transplantation : Official Journal of the Middle East Society for Organ Transplantation·Felix DondorfFalk Rauchfuss
Jun 6, 2020·Expert Opinion on Drug Metabolism & Toxicology·Jingheng WangTaosheng Chen
Sep 10, 2021·Annual Review of Pharmacology and Toxicology·Tatsuki FukamiMiki Nakajima

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