Association between Cytochrome P450 2D6 genetic polymorphisms and tramadol metabolism in Egyptian tramadol-intoxicated subjects

Abstract

Article history: Received 1 July 2019 Accepted 18 December 2019 There is substantial evidence for a causal relationship between genetic variability of the cytochrome P450 2D6 (CYP2D6) gene and changes in the pharmacokinetics of drugs. Polymorphic CYP2D6 activity has been shown to be a determinant of the pharmacokinetics and pharmacodynamics of tramadol via hepatic phase I O-demethylation of (+)-tramadol to (+)-O-desmethyltramadol. Several studies have demonstrated the impact of CYP2D6 polymorphism on the pharmacokinetics of tramadol. Hence, the aim of this study was to determine if the well documented pharmacokinetics of tramadol regarding CYP2D6 could be verified in a group of Egyptian abusers. The genotype-phenotype relationships were also assessed. A total of 83 tramadol intoxicated subjects who were referred to the Poison Control Center (PCC), Ain Shams University Hospitals, were enrolled in the present study. Urinary concentrations of tramadol (TMD), and its metabolites, O-desmethyltramadol M1 (ODT) and N-desmethyltramadol M2 (NDT) were determined using the Trace GC-TSQ mass spectrometer. CYP2D6 genotyping was performed using PGX-CYP2D6 Strip Assay. Through the use of CYP2D6 phenotyping, 10 patients (12.1 %) were classified as CYP2D6 poor metabolizers (PMs), and 73 (87.9 %) were genotyped as CYP2D6 extensive metabolizers (EMs), including 57 (68.7 %) homozygous EMs and 16 (19.2 %) heterozygous EMs. Median TMD level didn’t differ significantly between PMs and EMs (p = 0.356). Median M1 level was significantly higher in EMs than that in PMs (p = 0.001), while median M2 level didn’t differ significantly between PMs and EMs (p = 0.597). There were statistically significant differences in TMD/M1, TMD/M2 and M1/M2 ratios between PMs and EMs (p = 0.001). M1/M2, with an area under the ROC curve of 0.976, performed better than TMD/M1 (AUC = 0.724) and TDM/M2 (AUC = 0.656), in differentiating between EMs and PMs. The impact of the CYP2D6 polymorphism on the pharmacokinetics of tramadol was clearly demonstrated in a group of tramadolintoxicated Egyptian subjects.