MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine.
OBJECTIVE
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.
Drescher
Siegfried
S
Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376 Stuttgart, Germany.
Schaeffeler
Elke
E
Hitzl
Monika
M
Hofmann
Ute
U
Schwab
Matthias
M
Brinkmann
Ulrich
U
Eichelbaum
Michel
M
Fromm
Martin F
MF
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000097:blood* / Q000235:genetics; D019002:CD56 Antigen / Q000097:blood; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism; D019450:Genes, MDR; D005838:Genotype; D006634:Histamine H1 Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000097:blood; D020112:Rhodamine 123 / Q000378:metabolism; D012737:Sex Factors; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019002:CD56 Antigen; D005456:Fluorescent Dyes; D006634:Histamine H1 Antagonists; D012333:RNA, Messenger; D020112:Rhodamine 123; D016593:Terfenadine; C093230:fexofenadine