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: 3567.1t1535.5 vs 3910.1t1894.8 ng ml x1 h, NS; 95% CI on the difference x1364.9, 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: 45.6t7.2% vs 61.1t12.3%, 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.

Association of Multidrug Resistance in Epilepsy with a Polymorphism in the Drug-Transporter GeneABCB1

“…These findings were subsequently confirmed. 24 Leukocyte levels of ABCB1 messenger RNA showed a similar trend; the highest levels were in subjects with the CC genotype and the lowest levels in subjects with the TT genotype. Rhodamine transport is a robust marker of the drug-transport capacity of ABCB1.…”

Investigation of polymorphism in the MDR1 gene and antidepressant-induced mania

“…8 However, in a recent report, fexofenadine disposition was not significantly different between the CC and TT groups. 9 The Pharmacogenomics Journal (2003) 3,[297][298][299]While there is discrepancy in the reports on the relationship between the 3435C4T polymorphism and plasma concentration of P-gp substrate, the data on genotypedependent differences in duodenal absorption and P-gp efflux in peripheral blood cells [9][10][11] are much more consistent.…”

Functional Implications of Genetic Polymorphisms in the Multidrug Resistance Gene MDR1 (ABCB1)

“…A similar finding was made when the 2677 and No difference in transport of verapamil, digoxin, viblastine and cyclosporine A [35] 3435 polymorphisms were analyzed separately, with AUC values being highest for individuals carrying the reference alleles. However, in a separate study, the MDR1 C3435T variant had no effect on fexofenadine disposition (43). The contribution of MDR1 genetic polymorphisms has also been extensively studied for the calcineurin inhibitors cyclosporine and tacrolimus, which show large interindividual differences in oral bioavailability.…”