MDR1 C3435T 및 G2677T 유전적 다형성에 따른 Fexofenadine의 약동학 및 약력학적 분석

Pharmacokinetics and Pharmacodynamics of Fexofenadine in Relation to Genetic Polymorphism of MDR-1 C3435T/G2677T

Background : Multi-drug resistance 1 (MDR1) gene encoded P-glycoprotein(Pgp) contributes to the disposition of many substrate drugs. Recently, many reports have been described for the single nucleotide polymorphisms (SNPs) of MDR1 gene and their functional significances in vitro and in vivo. This study is to evaluate the effect of MDR1 C3435T/G2677T genetic polymorphism on the pharmacokinetics (PK) and pharmacodynamics (PD) of fexofenadine, a known Pgp substrate, in Korean healthy subjects. Methods : Fifteen male subjects whose MDRl C3435T/G2677T genotype was determined using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) method were enrolled (8 subjects with CC for 3435 and GG for 2677 ; 7 subjects with TT for 3435 and TT for 2677). After single oral dose of 120 mg fexofenadine, blood samples were serially drawn upto 24 hours. Histamine induced wheal and flare reaction test was also conducted for 3 hours after dosing to measure pharmacodynamic effect of fexofenadine. Concentrations of fexofenadine were analyzed with HPLC using fluorescence detector. Kinetic parameters were calculated by fitting the data to noncompartmental PK models using WinNonlin program. Results : The plasma concentrations of fexofenadine were higher, especially in absorptive phase, in subjects with 3435T/2677T haplotype than those in subjects with 3435C/2677G wild haplotype. Although there was no significant difference of pharmacokinetic parameters between genotype groups, area under the plasma concentration from 0 to $6(AUCe_{6hr})$ showed significant differences between genotype groups (p<0.05). The time course of wheal and flare suppression showed no statistical difference between genotype groups, but subjects with 3435T/2677T haplotype showed higher antihistamine effect that those with 3435C/2677G wild haplotype. Conclusions : These results suggest that MDR1 C3435T/G2677T genetic polymorphism seem likely to be associated with fexofenadine disposition, implying that SNPs at 2677 and 3435 may have an effect on Pgp expression or activity in the intestinal epithelium.