The effect of CYP2J2, CYP3A4, CYP3A5 and the MDR1 ^C3435T polymorphisms and gender on the urinary excretion of the metabolites of the H₁‐receptor antihistamine ebastine: a pilot study

Abstract

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 AimsTo 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. MethodsEighty-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 PCRrestriction 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 g rapefruit juice. ResultsWomen excreted statistically greater amounts of desalkylebastine in urine (mean ± SD (95% confidence intervals, 95% CI), 23.0 ± 19.5 (18.1, 27.9) µ mol) 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). ConclusionsGender and the presence of the MDR1 C3435T polymorphism both influence the excretion of ebastine metabolites in urine.

Polymorphisms of cytochrome P450 genes in three ethnic groups from Russia

“…For the Russians living in Kursk, the frequency of heterozygous genotype is quite low (2.3%) (37), which explains their similarity to Bashkirs and dissimilarities compared to Russians and Tatars inhabiting the Republic of Bashkortostan. For Russians and Tatars, the genotypes and alleles frequency distribution of the CYP2J2 was significantly different from Spaniards and Americans, but was similar to Germans (37,43,44). Bashkirs differed from all Caucasian populations.…”

“…The population of Caucasians, in contrast, is characterized by a higher frequency of the presence of heterozygous genotype CYP2J2*1*7 (41). Individuals with homozygous CYP2J2*7*7 genotype were found in Germans and Spaniards (0.7% and 3.9%, respectively) (37,42,43). For the Russians living in Kursk, the frequency of heterozygous genotype is quite low (2.3%) (37), which explains their similarity to Bashkirs and dissimilarities compared to Russians and Tatars inhabiting the Republic of Bashkortostan.…”

Drug interactions

“…Administration of grapefruit juice resulted in an approximately 25% statistically significant decrease in desalkylebastine (the CYP3A-generated metabolite) excretion in urine. In contrast to the results for desalkylebastine, the urinary excretion of the CYP2J2-generated metabolite, carebastine, was not substantially altered after grapefruit juice administration (Gervasini et al, 2006) (see Figure 13) Grapefruit juice does not reduce the oral bioavailability of desloratadine (Banfield, 2001), which is not a substrate for OATP-A (Favreau et al, 2003). The effect of grapefruit juice on cetirizine, levocetirizine, loratadine, and mizolastine has not been investigated.…”

Theranostics meets traditional Chinese medicine: rational prediction of drug–herb interactions

“…Reduced with the variant allele [162] Felodipine Grapefruit juice treatment significantly increased AUC 0-12 h of felodipine by 100% which was independent of CYP3A5*3 genotype…”