A variant 2677A allele of the MDR1 gene affects fexofenadine disposition.
OBJECTIVE
There have been considerable disagreements regarding the influence of MDR1 (ABCB1) 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 MDR1 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 MDR1 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 MDR1 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/mL versus 3315 +/- 958 ng . h/mL versus 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 MDR1 haplotypes and provide a plausible explanation for the conflicting results regarding the effect of MDR1 polymorphisms on the disposition of P-gp substrates.
Yi
So-Young
SY
Department of Pharmacology and Clinical Pharmacology Unit, Seoul National University College of Medicine and Hospital, Korea.
Hong
Kyoung-Sup
KS
Lim
Hyeong-Seok
HS
Chung
Jae-Yong
JY
Oh
Dal-Seok
DS
Kim
Jung-Ryul
JR
Jung
Hye-Ryung
HR
Cho
Joo-Youn
JY
Yu
Kyung-Sang
KS
Jang
In-Jin
IJ
Shin
Sang-Goo
SG
D000328:Adult; D000483:Alleles; D019540:Area Under Curve; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D019450:Genes, MDR / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D007723:Korea / Q000453:epidemiology; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
D006634:Histamine H1 Antagonists; D016593:Terfenadine; C093230:fexofenadine