Disease relevance of Carebastine

• OBJECTIVE: To assess the differences between patients with hepatic insufficiency and healthy subjects with regard to the pharmacokinetics, cardiac safety and overall safety of ebastine and its active metabolite carebastine [1].
• In a multicenter, multinational, double-blind, randomized, placebo-controlled study, patients with seasonal allergic conjunctivitis (SAC) were assigned an eye drop formulation of carebastine (25 mg/ml) or placebo [2].

High impact information on Carebastine

• Carebastine (10(-7) to 10(-6) mol/L) inhibited this upregulation [3].
• CONCLUSION: Ebastine can be safely administered to patients with impaired hepatic function, as no clinically important differences can be anticipated from the pharmacokinetics and safety profile of ebastine/carebastine as compared with healthy subjects [1].
• Therefore, no apparent accumulation of ebastine occurred, and steady-state concentrations of ebastine and carebastine were predictable from single-dose pharmacokinetics both in healthy subjects and in hepatically impaired patients [1].
• Ebastine is a novel histamine H1 receptor antagonist that combines potency with a rapid onset (fast absorption) and long duration (slow elimination) of action, at least partially mediated via the formation of an acid metabolite (carebastine) that is even more potent as an antihistamine [4].
• Carebastine inhibited the release of PGD2 (IC30 8.14 mumol/L) but had little effect on cytokine release [5].

Biological context of Carebastine

• The AUC of carebastine was not affected by cimetidine coadministration (4049 +/- 985 ng ml-1 h after cimetidine vs 3795 +/- 959 ng ml-1 h after placebo; 95% confidence interval of the difference: -412 to 919) [6].
• N-Dealkylation yielded des-BP, whereas M-OH, an hydroxylation product, could be further oxidized to the pharmacologically active carebastine [7].
• Genotype was correlated with the urinary excretion of the main ebastine metabolites (desalkylebastine and carebastine) under basal conditions and after administration of grapefruit juice [8].
• Statistically significant differences were observed in the representative parameters of the disposition kinetics of carebastine [9].
• Therefore, it may be concluded that administration with food maximizes the bioavailability of carebastine [10].

Anatomical context of Carebastine

• Therefore, we used human liver microsomes (HLMs) and expressed cytochromes P450 (P450s) to characterize the metabolism of ebastine and that of its metabolites, hydroxyebastine and carebastine [11].

Associations of Carebastine with other chemical compounds

• Ebastine is extensively and rapidly metabolised to its active metabolite; carebastine, has a half-life of approximately 15 hours and duration of action of at least 24 hours [12].

Gene context of Carebastine

• Although CYP3A4 and CYP2J2 have been implicated in ebastine N-dealkylation and hydroxylation, the enzyme catalyzing the subsequent metabolic steps (conversion of hydroxyebastine to desalkylebastine and carebastine) have not been identified [11].
• In conclusion, carebastine was shown to be a substrate for P-glycoprotein-mediated efflux from the brain at the BBB [13].
• Comparative pharmacokinetics of the histamine H1-receptor antagonist ebastine and its active metabolite carebastine in rats, guinea pigs, dogs and monkeys [14].

Analytical, diagnostic and therapeutic context of Carebastine

• These findings strongly indicate that carebastine is responsible for the antihistamine activity after oral administration of ebastine [14].
• The ratio of the arterial blood concentration of carebastine during intraportal infusion to that during intravenous infusion was 1.88, suggesting the single-pass metabolic conversion in the liver [15].
• In contrast, terfenadine carboxylate (100 mg/kg i.v.), norastemizole (20 mg/kg, i.v.) and carebastine (50 mg/kg, i.v.), the major metabolites of terfenadine, astemizole and ebastine, were largely devoid of adverse ECG effects [16].

References