The mutant a allele function in exon 21 G2677T/A of human MDR1 gene

There are still contradictory reports on the relationship between the MDR1 genotype and disposition of the PGP substrates. The allele frequency for the mutant A allele of the exon 21 G2677T/A (Ala 893Ser/Thr) is about 20% in Asian groups but the frequencies are negligible in the Caucasian and African populations. We hypothesized that as yet unknown A allele function was the one of reasons of contradictory results. This study was performed to clarify the effects of the major MDR1 gene polymorphisms including a mutant A allele in exon 21 on the fexofenadine pharmacokinetics. A single oral dose of 180 mg fexofenadine HCl was administered in 33 healthy Korean male volunteers, who were divided into 6 groups on the basis of the MDR1 haplotype for G2677T/A and C3435T polymorphism. A significant relationship was observed between genotypes and AUCs (p<0.05). 2677AA/3435CC subject group (n=3) showed significant lower AUC(0–24) values than those of other 5 groups (2677/3435: GG/CC, GT/CT, TT/TT, GA/CC, TA/CT). Homozygous 3435TT subjects had significant higher AUC(0–24) and Cmax values than CC subjects who were stratified for genotypes at position 3435 [AUC(0–24) 5934 +/‐ 2064 ng*hr/mL vs 3998 +/‐ 1241 ng*hr/mL, Cmax 958 +/‐ 408 ng/mL vs 673 +/‐ 242 ng/mL; mean +/‐ SD]. It was thought that the A allele variant in exon 21 had more powerful efflux function of PGP than wild type or T allele variant. Clinical Pharmacology & Therapeutics (2004) 75 , P68–P68; doi: 10.1016/j.clpt.2003.11.255