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Effect of itraconazole on the pharmacokinetics and pharmacodynamics of fexofenadine in relation to the MDR1 genetic polymorphism
Author(s) -
Shon JiHong,
Yoon YoungRan,
Hong WonSeok,
Nguyen Phuc Minh,
Lee SangSeop,
Choi YoungGil,
Cha InJun,
Shin JaeGook
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.04.012
Subject(s) - fexofenadine , pharmacokinetics , itraconazole , pharmacology , crossover study , loratadine , pharmacodynamics , medicine , placebo , terfenadine , chemistry , antifungal , alternative medicine , pathology , dermatology
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‐∞ ) 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‐∞ 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. Conclusion 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. Clinical Pharmacology & Therapeutics (2005) 78 , 191–201; doi: 10.1016/j.clpt.2005.04.012