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

Br J Clin Pharmacol. 2002 May;53(5):526-34. doi: 10.1046/j.1365-2125.2002.01591.x.


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,infinity) 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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / blood*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • CD56 Antigen / blood
  • Female
  • Fluorescent Dyes / metabolism
  • Genes, MDR*
  • Genotype
  • Histamine H1 Antagonists / blood
  • Histamine H1 Antagonists / pharmacokinetics*
  • Histamine H1 Antagonists / urine
  • Humans
  • In Vitro Techniques
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Polymorphism, Genetic*
  • RNA, Messenger / blood
  • Rhodamine 123 / metabolism
  • Sex Factors
  • Terfenadine / analogs & derivatives*
  • Terfenadine / blood
  • Terfenadine / pharmacokinetics*
  • Terfenadine / urine


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • CD56 Antigen
  • Fluorescent Dyes
  • Histamine H1 Antagonists
  • RNA, Messenger
  • Rhodamine 123
  • Terfenadine
  • fexofenadine