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. 2006 Aug;62(2):177-86.
doi: 10.1111/j.1365-2125.2006.02578.x.

The effect of CYP2J2, CYP3A4, CYP3A5 and the MDR1 polymorphisms and gender on the urinary excretion of the metabolites of the H-receptor antihistamine ebastine: a pilot study

Guillermo Gervasini  1 , Sonia Vizcaino, Juan Antonio Carrillo, Maria Jesus Caballero, Julio Benitez
Affiliations

The effect of CYP2J2, CYP3A4, CYP3A5 and the MDR1 polymorphisms and gender on the urinary excretion of the metabolites of the H-receptor antihistamine ebastine: a pilot study

Guillermo Gervasini et al. Br J Clin Pharmacol. 2006 Aug.

Abstract

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) micromol) 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.

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Figures

Figure 1
Figure 1
Pathways of ebastine metabolism
Figure 2
Figure 2
Genotype–phenotype associations between the amounts of desalkylebastine (A) and carebastine (B) excreted in the urine and the CYP2J2*7, CYP3A4*1B, CYP3A5*3 and MDR1C3435T polymorphisms. (*) P < 0.05
Figure 3
Figure 3
Genotype–phenotype associations between fold-changes (day 1/day 7) in the amounts of desalkylebastine excreted in the urine and CYP2J2*7, CYP3A4*1B, CYP3A5*3 and MDR1C3435T polymorphisms following administration of grapefruit juice. (**) P = 0.01
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