Metabolism of the analgesic flupirtin in man

Abstract

Flupirtin (FLU) is a non‐opiotic analgetic drug used to relieve acute and chronic pain. Recently, FLU was suspected to cause liver damage as detected by an elevation of hepatic transaminases. However, the biochemical mechanism behind this is unknown; furthermore, the metabolism of FLU is known only in part. Therefore, we evaluated drug metabolism in vitro and metabolic disposition of the drug in man using a metabolomics approach. Healthy volunteers received an oral administration of FLU (100 mg/day) over a period of 5 days. The metabolic pattern in urine collected within this interval was compared with a blank urine sample before treatment. Mass spectrometric techniques were performed using urine fractions at pH = 6 and pH = 10. For estimating the influence of glucuronidation of FLU and its main metabolite D‐13223 in detail, recombinant expressed human UGT isoenzymes were used for competition assays between FLU and their specific substrates. In urine, FLU, D‐13223, the N oxidized metabolites of FLU and D‐13223 as well as two, so far not described, N‐glucuronides and mercapturic acid derivatives were detected. Furthermore, FLU did not substantially inhibit the enzymatic activity of UGT1A isoenzymes, however, 300 µM FLU lead to a small but significant reduction of UGT2B7 and 2B15 activities. In addition to known metabolites Flupirtin is metabolized to glucuronides and glutathione adducts in man.