Effect of itraconazole on the pharmacokinetics and pharmacodynamics of fexofenadine in relation to the MDR1 genetic polymorphism.
OBJECTIVE
Our objective was to evaluate the effect of itraconazole, a P-glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of fexofenadine, a P-glycoprotein substrate, in relation to the multidrug resistance 1 gene (MDR1) G2677T/C3435T haplotype.


METHODS
A single oral dose of 180 mg fexofenadine was administered to 7 healthy subjects with the 2677GG/3435CC (G/C) haplotype and 7 with the 2677TT/3435TT (T/T) haplotype. One hour before the fexofenadine dose, either 200 mg itraconazole or placebo was administered to the subjects in a double-blinded, randomized, crossover manner with a 2-week washout period. Histamine-induced wheal and flare reactions were measured to assess the effects on the antihistamine response.


RESULTS
In the placebo phase, pharmacokinetic parameters of fexofenadine showed no statistically significant difference between 2 MDR1 haplotypes; the area under the curve from time 0 to infinity (AUC(0-infinity)) of fexofenadine in the T/T and G/C groups was 5194.0 +/- 1910.8 and 4040.4 +/- 1832.2 ng.mL(-1).h(-1), respectively (P = .271), and the oral clearance (CL/F) was 530.9 +/- 191.1 and 806.0 +/- 355.3 mL.h(-1).kg(-1), respectively (P = .096). The disposition of itraconazole, a substrate of P-glycoprotein, was not significantly different between the 2 haplotypes. After itraconazole pretreatment, however, the differences in fexofenadine pharmacokinetics became statistically significant; the mean fexofenadine AUC(0-infinity) in the T/T group was significantly higher than that in the G/C group (15,630.6 +/- 5070.0 and 9252.9 +/- 2044.1 ng/mL.h, respectively; P = .007), and CL/F of the T/T subjects was lower than that of the G/C subjects (167.0 +/- 33.3 and 292.3 +/- 42.2 mL.h(-1).kg(-1), respectively; P < .001). Itraconazole pretreatment caused more than a 3-fold increase in the peak concentration of fexofenadine and the area under the curve to 6 hours compared with the placebo phase. This resulted in a significantly higher suppression of the histamine-induced wheal and flare reactions in the itraconazole pretreatment phase compared with those in the placebo phase.


CONCLUSIONS
The effect of MDR1 G2677T/C3435T haplotypes on fexofenadine disposition are magnified in the presence of itraconazole. Itraconazole pretreatment significantly altered the disposition of fexofenadine and thus its peripheral antihistamine effects.
Shon
Ji-Hong
JH
Department of Pharmacology, PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Korea.
Yoon
Young-Ran
YR
Hong
Won-Seok
WS
Nguyen
Phuc Minh
PM
Lee
Sang-Seop
SS
Choi
Young-Gil
YG
Cha
In-Jun
IJ
Shin
Jae-Gook
JG
D000328:Adult; D000935:Antifungal Agents / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D019450:Genes, MDR; D006239:Haplotypes; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D008297:Male; D011110:Polymorphism, Genetic; D016593:Terfenadine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D000935:Antifungal Agents; D006634:Histamine H1 Antagonists; D017964:Itraconazole; D016593:Terfenadine; C093230:fexofenadine