CYP3A4 and CYP2C19 genetic polymorphisms and zolpidem metabolism in the Chinese Han population: a pilot study

Abstract

Zolpidem (ZPD) is an imidazopyridine hypnotic and little is known about the pharmacogenetics of ZPD. Our objective was to evaluate inter-individual genetic variation in conjunction with metabolic ratios of ZPD found in a toxicological analysis. Healthy individuals (n=300) were genotyped for CYP2D6, CYP2C19, CYP2C9, CYP3A4 and CYP1A2 by allele-specific primer extension followed by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS). Twenty-four Chinese volunteers were chosen and divided into the following four groups (n=6/group): group 1: CYP3A4*18 (wild-type, W), CYP2C19*2 (W); group 2: CYP3A4*18 (mutant, M), CYP2C19*2 (W); group 3: CYP3A4*18 (W), CYP2C19*2 (M); and group 4: CYP3A4*18 (M), CYP2C19*2 (M). ZPD and its major metabolites zolpidem 6-carboxylic acid (ZCA) and zolpidem phenyl-4-carboxylic acid (ZPCA) were determined after oral administration of ZPD (10mg), using an UPLC-MS/MS method. Positive correlations between CYP3A4 and CYP2C19 alleles and ZPD metabolism were found. The results of this study show that CYP3A4*18 increases CYP3A4 activity while CYP2C19*2 reduces CYP2C19 activity; the latter mutation is associated with the poor metabolism of ZPD in the Chinese Han population. The results also suggest that genetic factors play a major role in the metabolism of individual drugs with implications for both forensic science and clinical pharmacogenetics.