期刊
CLINICAL PHARMACOLOGY & THERAPEUTICS
卷 76, 期 5, 页码 418-427出版社
WILEY
DOI: 10.1016/j.clpt.2004.08.002
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Background and Objectives: There have been considerable disagreements regarding the influence of MDRI (ABCBI) polymorphisms on the disposition of P-glycoprotein (P-gp) substrates. We speculated that the unknown function of the A allele of exon 21 G2677T/A (Ala893Ser/Thr) provides one of the reasons for the contradictory results. This study was performed to clarify the effects of major MDRI gene polymorphisms, including a variant A allele in exon 21, on fexofenadine pharmacokinetics. Methods. We investigated the occurrence of 3 high-frequency single-nucleotide polymorphisms (SNPs) in exons 12 (C1236T), 21 (G2677T/A), and 26 (C3435T) of the MDRI gene in 232 healthy Koreans, using a polymerase chain reaction-restriction fragment length polymorphism method, and performed haplotype analysis on these 3 SNPs. A single oral dose of 180 mg fexofenadine hydrochloride was administered to 33 healthy Korean male volunteers, who were divided into 6 groups based on the MDRI genotype for the G2677T/A polymorphism in exon 21 and the C3435T polymorphism. in exon 26. Results. A strong linkage disequilibrium was observed among the 3 SNPs. The frequencies of the 4 major haplotypes, 1236C-2677A-3435C, C-G-C, T-G-C, and T-T-T, were 16.4%, 18.6%, 21.6%, and 32.2%, respectively. Fexofenadine disposition varied considerably among the groups. In the 2677AA/3435CC genotype group (n = 3), the values of area under the concentration-time curve from time 0 to 24 hours [AUC(0-24)] were significantly lower (P = .014) than those of the other 5 genotype groups (GG/CC, GT/CT, TT/TT, GA/CC, and TA/CT). As compared with the 2677GG/3435CC subjects, the AUC(0-24) values were 17% lower in the 2677AA/3435CC subjects and 47% higher in the 2677TT/3435TT subjects (GG/CC versus AA/CC versus TT/TT, 4017 +/- 1137 ng(.)h/mLversus 3315 958 ng - h/mLversus 5934 +/- 2,064 ng(.)h/mL; P = .018). By stratification for genotypes at position 3435, homozygous 3435TT subjects were found to have significantly higher AUC(0-24) (P = .024) and maximum plasma concentration (P = .040) values than CC subjects [AUC(0-24), 5934 +/- 2064 ng(.)h/mL versus 3998 +/- 1241 ng(.)h/mL; maximum plasma concentration, 958 +/- 408 ng/mL versus 673 +/- 242 ng/mL]. Conclusions: The plasma concentrations of fexofenadine after a single oral administration were lower in 2677AA/3435CC subjects than in subjects with the other 5 genotype combinations of the SNPs of G2677T/A and C3435T. These findings confirm the importance of analyzing MDRI haplotypes and provide a plausible explanation for the conflicting results regarding the effect of MDRI polymorphisms on the disposition of P-gp substrates.
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