Cyp2d6*10 Allele Has Significant Effects on The Pharmacokinetics of Tramadol and Its Metabolite

Abstract

Tramadol is a centrally acting analgesic used to treat moderate to severe pain. Tramadol exerts its activity by binding to the μ-opioid receptor and inhibiting the reuptake of serotonin and norepinephrine. Tramadol is metabolized to its active metabolite, Ο-desmethyltramadol, by CYP2D6. About 20 to 30% of drugs in clinical use are metabolized by CYP2D6 and CYP2D6 genetic polymorphism have been associated with altered enzyme activity. As CYP2D6*10 allele is the most common allele in the Asian population, we investigated the effect of CYP2D6*10 allele on the pharmacokinetics of tramadol and its active metabolite. Forty-four healthy Korean subjects were recruited and divided into 3 different groups according to CYP2D6 genotype: CYP2D6*wt/*wt (*w t= *1 or *2, n = 15), CYP2D6*wt/*10 (n = 14) and CYP2D6*10/*10 (n = 15). After overnight fasting, each subject received a single oral dose of 100 mg tramadol. Blood samples were collected up to 30 hours after drug intake, and plasma concentrations of tramadol and its metabolite were determined by using validated liquid chromatography-tandem mass spectrometry system. Although Cmax of tramadol was not significantly different among 3 different groups, AUC0-∞ of tramadol in CYP2D6*10/*10 group was 1.56-fold higher than that in CYP2D6*wt/*wt group (P < 0.001) and apparent oral clearance (CL/F) of tramadol in CYP2D6*10/*10 group was 32.9% lower, compared to CYP2D6*wt/*wt group. In terms of its active metabolite, Cmax and AUC0-∞ in CYP2D6*10/*10 group were significantly higher than those in CYP2D6*wt/*wt group (both, P < 0.001). CYP2D6*10 allele has significant effects on the plasma exposure of tramadol and its active metabolite.