Metabolic activation and analgesic effect of flupirtine in healthy subjects, influence of the polymorphic NAT2, UGT1A1 and GSTP1

Abstract

Aims: The rare association of flupirtine with liver injury is most likely caused by reactive quinone diimines and their oxidative formation may be influenced by the activities of N-acetyltransferases (NAT) that conjugate the less toxic metabolite D13223, and by glucuronosyltransferases (UGT) and glutathione S-transferases (GST) that generate stable terminal glucuronides and mercapturic acid derivatives, respectively. The influence of genetic polymorphisms of NAT2, UGT1A1 and GSTP1 on generation of the terminal mercapturic acid derivatives and analgesic effects was evaluated to identify potential genetic risk factors for hepatotoxicity of flupirtine.

Methods: Metabolic disposition of flupirtine was measured after intravenous administration (100 mg), after swallowing an immediate-release (IR) tablet (100 mg) and after repeated administration of modified release (MR) tablets (400 mg once daily 8 days) in 36 selected healthy subjects. Analgesic effects were measured using pain models (delayed onset of muscle soreness, electric pain).

Results: Flupirtine IR was rapidly but incompletely absorbed (∼ 72%). Repeated administration of flupirtine MR showed lower bioavailability (∼ 60%). Approximately 12% of bioavailable flupirtine IR and 8% of bioavailable flupiritine MR was eliminated as mercapturic acid derivatives into the urine independent of the UGT1A1, NAT2 and GSTP1 genotype. Carriers of variant GSTP1 alleles showed lower bioavailability but increased intestinal secretion of flupirtine and increased efficiency in experimental pain. Flupirtine was not a substrate for ABCB1 and ABCC2.

Conclusions: Formation of mercapturic acid derivatives is a major elimination route for flupirtine in man. However, the theoretically toxic pathway is not influenced by the frequent polymorphisms of UGT1A1, NAT2 and GSTP1.

Keywords: ABCB1; ABCC2; drug-induced liver disease; flupirtine; pharmacogenetics; quinone diimines.

Figure 1

Theoretical metabolism of flupirtine in man (modified from Methling et al. 2009 19). POD, peroxidase; NAT, N-acetyltransferase; UGT, UDP-glycuronosyltransferase; GSH, gluthathione; D13223, major N-actylated metabolite of flupirtine in man; M424 and M466, mercapturic acid derivatives of the quinone diimine

Figure 2

Concentration–time curves of flupirtine and its acetylated metabolite D13223 after intravenous flupirtine infusion and single dosing of flupirtine IR (A) and after chronic administration of flupirtine MR in 24 healthy subjects (B). , flupirtine i.v.; , flupirtine IR; , D13223 i.v.; , D13223 (IR); , flupirtine MR; , D13223

Figure 3

Concentration–time curves of flupirtine (A) and the acetylated metabolite D13223 (B) after intravenous flupirtine infusion, single dosing of flupirtine IR and chronic administration of flupirtine MR in 12 healthy carriers of variant alleles of the glutathione-S-transferase P1 (GST-) and 24 carriers of wild-type alleles (GST+). , GST+; , GST−

Figure 4

Effects of intravenous flupirtine (100 mg), single dosing of flupirtine IR (100 mg) and chronic administration of flupirtine MR (400 mg) on electric pain threshold (A) and delayed onset of muscle soreness (DOMS, B) in 12 healthy carriers of variant alleles of the glutathione-S-transferase P1 (GST-) and 24 carriers of wild-type alleles (GST+). Higher pain threshold (electric pain) or lower values on a visual analogue scale (VAS-DOMS) refer to stronger analgesic effect of flupirtine