Investigation of the differences in the pharmacokinetics of CYP2D6 substrates, desipramine and dextromethorphan in healthy African subjects carrying the allelic variants CYP2D6*17 and CYP2D6*29 when compared with normal metabolizers

This study investigated the differences in the pharmacokinetics (PK) of dextromethorphan and desipramine in African healthy volunteers to understand the effect of allelic variants of the human cytochrome-P450(CYP)2D6 enzyme namely, CYP2D6*1/*2 diplotypes, CYP2D6*17*17 and CYP2D6*29*29 genotypes. Overall, 28 adults were included through genotype screening into the three cohorts: CYP2D6*1/*2 (n = 12), CYP2D6*17*17 (n = 12), and CYP2D6*29*29 (n = 4). Each subject received a single oral dose of dextromethorphan 30-mg syrup on Day 1 and desipramine 50-mg tablet on Day 8. The PK parameters, area under plasma concentration-time curve from time of dosing to time of last quantifiable concentration (AUClast) and extrapolated to infinity (AUCinf), and maximum plasma concentration (Cmax) were determined. For both dextromethorphan and desipramine, AUCinf and Cmax were higher in subjects of the CYP2D6*29*29 and CYP2D6*17*17 cohorts as compared with those reported in the CYP2D6*1/*2 diplotype cohort, and for normal metabolizers in literature. All PK parameters including AUCinf, Cmax, and elimination half-life followed a similar trend: CYP2D6*17*17 >CYP2D6*29*29 >CYP2D6*1/*2. The plasma and urinary drug/metabolite exposure ratios of both drugs were higher in subjects of the CYP2D6*17*17 and CYP2D6*29*29 cohorts when compared with those in the CYP2D6*1/*2 diplotype cohort. All adverse events were mild, except for one subject with CYP2D6*17*17 who had moderately severe headache with desi...
Source: The Journal of Clinical Pharmacology - Category: Drugs & Pharmacology Authors: Source Type: research