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 interindividual variability in loratadine pharmacokinetics and the greater genetically determined variability of CYP2D6 activity than of 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 of 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 high-performance liquid chromatography. 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 versus 11.06 ± 1.70 versus 14.59 ± 2.43 l/h/kg, respectively [one-way analysis of variance (ANOVA), p < 0.01], and the corresponding metabolic ratios [area under the plasma concentration-time curve (AUC)_{desloratadine}/AUC_loratadine] were 1.55 ± 0.73 versus 2.47 ± 0.46 versus 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.