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The effect of CYP2J2, CYP3A4 , CYP3A5 and the MDR1 C3435T polymorphisms and gender on the urinary excretion of the metabolites of the H 1 ‐receptor antihistamine ebastine: a pilot study
Author(s) -
Gervasini Guillermo,
Vizcaino Sonia,
Carrillo Juan Antonio,
Caballero Maria Jesus,
Benitez Julio
Publication year - 2006
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2006.02578.x
Subject(s) - metabolite , excretion , urine , medicine , endocrinology , grapefruit juice , cyp3a4 , genotype , pharmacokinetics , cyp3a5 , chemistry , biology , metabolism , biochemistry , cytochrome p450 , gene
Aims To determine the effect of gender and the genetic polymorphisms of CYP2J2, CYP3A4, CYP3A5 and MDR1 on the urinary excretion of the H 1 antihistamine ebastine in healthy subjects. Methods Eighty‐nine Caucasians were studied. The presence of polymorphisms in genes known to be involved in ebastine metabolism and transport ( CYP2J2 * 2, * 3, * 4, * 6, * 7, CYP3A4 * 1B , CYP3A5 * 3 , * 6 and MDR1(ABCB1) C3435T ) was assessed by means of PCR‐restriction fragment length polymorphism and sequencing methods. Genotype was correlated with the urinary excretion of the main ebastine metabolites (desalkylebastine and carebastine) under basal conditions and after administration of grapefruit juice. Results Women excreted statistically greater amounts of desalkylebastine in urine (mean ± SD (95% confidence intervals, 95% CI), 23.0 ± 19.5 (18.1, 27.9) µmol) than men (12.4 ± 11.0 (7.9, 16.9)), (mean difference: 10.6 (2.4, 18.7), P < 0.005). The CYP2J2 , CYP3A4 and CYP3A5 analysed polymorphisms did not greatly affect ebastine metabolite excretion. The MDR1 C3435T polymorphism was found to affect both the urinary excretion of the active metabolite carebastine (32.3 ± 18.3 (23.1, 41.4), 22.8 ± 14.7 (18.6, 27.0) and 21.5 ± 15.3 (14.7, 28.3) for CC , CT and TT carriers, respectively; P < 0.05) and the grapefruit juice‐induced inhibition of its transport/formation (mean fold‐decrease ± SD (95% CI), 1.5 ± 0.8 (1.0, 2.0), 1.1 ± 0.9 (0.7, 1.4) and 0.9 ± 0.4 (0.6, 1.2) for CC , CT and TT carriers, respectively; P = 0.01). Conclusions Gender and the presence of the MDR1 C3435T polymorphism both influence the excretion of ebastine metabolites in urine.