Received for publication April 6, 2005.
Revised May 25, 2005.
Accepted for publication May 26, 2005.

Effect of CYP2D6*10 allele on the pharmacokinetics of loratadine in Chinese subjects

Abstract

Loratadine is known to be a substrate for both CYP3A4 and CYP2D6 based on a previous in vitro study. In view of the large inter-individual variability in loratadine pharmacokinetics and the greater genetically-determined variability of CYP2D6 activity than CYP3A4 in vivo, we hypothesized that CYP2D6 polymorphisms may contribute to the pharmacokinetic variability of loratadine. The purpose of this study was to evaluate the effect of CYP2D6 genotype (specifically the CYP2D6*10 allele) on the pharmacokinetics of loratadine in Chinese subjects. Three groups of healthy male Chinese subjects were enrolled: group I, homozygous CYP2D6*1 (*1/*1, n=4); group II, heterozygous CYP2D6*10 (*1/*10 or *2/*10, n=6); and group III, homozygous CYP2D6*10 (*10/*10, n=7) carriers. Each subject received a single oral dose of 20 mg loratadine under fasting conditions. Multiple blood samples were collected over 48 h, and the plasma concentrations of loratadine and its metabolite desloratadine were determined by HPLC. In comparing homozygous CYP2D6*10 (group III) to heterozygous CYP2D6*10 (group II) to homozygous CYP2D6*1 (group I) subjects, loratadine oral clearance values were 7.17 ± 2.54 vs 11.06 ± 1.70 vs 14.59 ± 2.43 L/h/kg respectively (one-way ANOVA, p<0.01), and the corresponding metabolic ratios (AUC_{desloratadine}/AUC_loratadine) were 1.55 ± 0.73 vs 2.47 ± 0.46 vs 3.32 ± 0.49 respectively (one-way ANOVA, p<0.05), indicating a gene-dose effect. The results demonstrated that CYP2D6 polymorphism prevalent in the Chinese population significantly affected loratadine pharmacokinetics.

Key words: human CYP enzymes, human pharmacokinetics