Changes in tramadol enantioselective pharmacokinetics and metabolism in rats with experimental diabetes treated or not with insulin

Abstract

This study aimed to investigate the impact of diabetes treated or not with insulin in the enantioselective pharmacokinetics of tramadol (trans-T) and its phase 1 metabolites O-desmethyltramadol (M1) and N-desmethyltramadol (M2). The CYP2D inhibitor quinidine was used to simulate the poor metabolizer phenotype. Male Wistar rats were divided into groups: control, quinidine (80-mg/kg quinidine intraperitoneally 4 h before trans-T), diabetic (45-mg/kg STZ i.v.), diabetes + insulin (2 IU/day insulin for 12 days), diabetes + quinidine and diabetes + insulin + quinidine. All animals (n = 6, per sampling time) received 20-mg/kg trans-T orally. The kinetic disposition of trans-T is enantioselective in control with higher AUC of (+)-trans-T than for its antipode. Quinidine reduced AUC ratios (+)-M1/(+)-trans-T and (-)-M1/(-)-trans-T compared to Control. Diabetes increased plasma concentrations of (+)-trans-T, (-)-trans-T, (+)-M1, (-)-M1 and (+)-M2 compared to control, but without changing AUC ratios M1/trans-T or M2/trans-T. Insulin reverted the effect of diabetes only for (-)-trans-T. The simulated diabetes in CYP2D poor metabolizers showed reduced metabolic ratios for M1 enantiomers. In conclusion, diabetes resulted in higher plasma concentrations of the active (+)-trans-T, (-)-trans-T and (+)-M1, suggesting down-regulation of CYP3A and OCT1. The glycemic control of diabetes by insulin reduces partially the impact of diabetes on trans-T pharmacokinetics.

Keywords: CYP2D; Diabetes; Enantiomers; Pharmacokinetics; Tramadol.