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.
OBJECTIVE
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.
Gervasini
Guillermo
G
Department of Pharmacology and Psychiatry, Medical School and Clinical Pharmacology Unit, Infanta Cristina University Hospital, University of Extremadura, E-06071-Badajoz, Spain. ggervasi@unex.es
Vizcaino
Sonia
S
Carrillo
Juan Antonio
JA
Caballero
Maria Jesus
MJ
Benitez
Julio
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001628:Beverages; D001835:Body Weight; D002090:Butyrophenones / Q000008:administration & dosage / Q000378:metabolism / Q000652:urine*; D032083:Citrus paradisi; D000090762:Cytochrome P-450 CYP2J2; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005838:Genotype; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000652:urine*; D006801:Humans; D008297:Male; D010105:Oxygenases / Q000235:genetics; D010865:Pilot Projects; D010880:Piperidines / Q000008:administration & dosage / Q000378:metabolism / Q000652:urine*; D012150:Polymorphism, Restriction Fragment Length; D012737:Sex Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002090:Butyrophenones; C000717350:CYP2J2 protein, human; D006634:Histamine H1 Antagonists; D010880:Piperidines; C058251:carebastine; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C510164:CYP3A5 protein, human; D000090762:Cytochrome P-450 CYP2J2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C058249:ebastine