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

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.

DOI: 10.1046/j.1365-2125.2002.01591.x

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