MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine

ABSTRACT

Aims The C3435T polymorphism in the human MDR1 gene is associated with lower intestinal P-glycoprotein expression, reduced protein function in peripheral blood cells and higher plasma concentrations of the P-glycoprotein substrate digoxin. Using fexofenadine, a known P-glycoprotein substrate, the hypothesis was tested whether this polymorphism also affects the disposition of other drugs in humans.

Methods Ten Caucasian subjects homozygous for the wild-type allele at position 3435 (CC) and 10 individuals homozygous for T at position 3435 participated in this study. A single oral dose of 180 mg fexofenadine HCl was administered. Plasma and urine concentrations of fexofenadine were measured up to 72 h using a sensitive LC/MS method. In addition, P-glycoprotein function was assessed using efflux of the P-glycoprotein substrate rhodamine 123 from CD56⁺ cells.

Results  Fexofenadine plasma concentrations varied considerably among the study population. However, fexofenadine disposition was not significantly different between the CC and TT groups (e.g. AUC(0,∞) CC vs TT: 3567.1±1535.5 vs 3910.1±1894.8 ng ml⁻¹ h, NS; 95% CI on the difference −1364.9, 2050.9). In contrast, P-glycoprotein function was significantly decreased in CD56⁺ cells of the TT compared with the CC group (rhodamine fluorescence CC vs TT: 45.6±7.2% vs 61.1±12.3%, P<0.05; 95% CI on the difference 5.6, 25.5).

Conclusions  In spite of MDR1 genotype-dependent differences in P-glycoprotein function in peripheral blood cells, there was no association of the C3435T polymorphism with the disposition of the P-glycoprotein substrate fexofenadine in this German Caucasian study population. These data indicate that other mechanisms including uptake transporter function are likely to play a role in fexofenadine disposition.