Ebastine의 약동학에 미치는 Telmisartan의 영향
Effect of Telmisartan on the Pharmacokinetics of Ebastine
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Purpose: Telmisartan, an angiotensin receptor blocker has been known to be a potent blocker of both CYP2J2 and Pglycoprotein(P-gp) in vitro. This study aims to investigate the drug-drug interactions between telmisartan and ebastine,a CYP2J2 and P-gp substrate in rats. Method: Ebastine (10 mg/kg) was orally given in the presence and absence oftelmisartan (4 mg/kg, p.o.). Heparinized blood was serially taken and the plasma concentrations of ebastine and its threemetabolites (hydroxyebastine, carebastine and desalkylebastine) were determined using LC-MS/MS, and their pharmacokineticparameters were compared. Results: Peak concentrations (Cmax) and AUC of ebastine were significantly (p<0.05)increased in the presence of telmisartan by 2.1 and 1.9 times, respectively. While Cmax of hydroxyebastine was significantlyincreased by 1.9 times, the half-life of hydroxyebasteine was decreased significantly with telmisartan (p<0.05). There was no change in the pharmacokinetic parameters of carebastine, the active metabolite of ebastine, and desalkylebastinewas not detected in plasma. The systemic exposure of ebastine was significantly augmented by telmisartan, indicatingthat telmisartan may enhance the absorption of ebastine by blocking P-gp. Conclusion: Although telmisartanmay also partially contribute to inhibit the biotransformation to hydroxyebastine, the inhibitory action seemed to beoverridden by the enhancement of absorption, because the generation of hydroxyebastine was not diminished. In spiteof such interactions between telmisartan and ebastine, no clinical consequence could be expected due to no significantchange of the active metabolite, carebastine.
Abstract
Purpose: Telmisartan, an angiotensin receptor blocker has been known to be a potent blocker of both CYP2J2 and Pglycoprotein(P-gp) in vitro. This study aims to investigate the drug-drug interactions between telmisartan and ebastine,a CYP2J2 and P-gp substrate in rats. Method: Ebastine (10 mg/kg) was orally given in the presence and absence oftelmisartan (4 mg/kg, p.o.). Heparinized blood was serially taken and the plasma concentrations of ebastine and its threemetabolites (hydroxyebastine, carebastine and desalkylebastine) were determined using LC-MS/MS, and their pharmacokineticparameters were compared. Results: Peak concentrations (Cmax) and AUC of ebastine were significantly (p<0.05)increased in the presence of telmisartan by 2.1 and 1.9 times, respectively. While Cmax of hydroxyebastine was significantlyincreased by 1.9 times, the half-life of hydroxyebasteine was decreased significantly with telmisartan (p<0.05). There was no change in the pharmacokinetic parameters of carebastine, the active metabolite of ebastine, and desalkylebastinewas not detected in plasma. The systemic exposure of ebastine was significantly augmented by telmisartan, indicatingthat telmisartan may enhance the absorption of ebastine by blocking P-gp. Conclusion: Although telmisartanmay also partially contribute to inhibit the biotransformation to hydroxyebastine, the inhibitory action seemed to beoverridden by the enhancement of absorption, because the generation of hydroxyebastine was not diminished. In spiteof such interactions between telmisartan and ebastine, no clinical consequence could be expected due to no significantchange of the active metabolite, carebastine.
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