复方氯雷他定缓释片人体药代动力学研究

Study on the Pharmacokinetics of Pesudoephedrine/Loratadine Extended-release Tablet in Healthy Volunteers

复方氯雷他定 (loratadine/pseudoephedrine)缓释片是治疗感冒引起的上呼吸道症状及过敏性鼻炎的药物 ,规格为每片含氯雷他定 5mg和硫酸伪麻黄碱 1 2 0mg。本研究建立了同时测定血浆中伪麻黄碱、氯雷他定及代谢物浓度的方法。该方法可用于研究健康受试者口服复方氯雷他定制剂后伪麻黄碱、氯雷他定及其代谢物的体内经时过程 ,为新药开发及临床用药提供参考和指导。

The extended-release pesudoephedrine/loratadine twice-daily combination tablet formulation has been shown to be safe and effective for the relief of symptoms associated with allergic rhinitis. Each tablet consists of laratadine 5 mg in an immediate-release coating and pseudoephedrine sulfate 120 mg, of which 60 mg i s in a barrier-protected core. We have established an LC-ESI-MS method for si multaneous determination of pesudoephedrine/loratadine and its metabolite(DCL) i n human plasma, which was proved to be sensitive,accurate and convenient. By th is means, we have investigated the characteristic of its pharmacokinetics in hum an. In the two study periods, subjects received a single dose and multiple doses (days 1 to 6) of twice-daily formulation. After a single dose, the main pharm acokinetics parameters of t 1/2, t max, c max, and A UC 0-36 were (6.9±1.4)h,(4.3±3.2)h ,(311.3±50.2)μg·L -1 a nd(4 312±678)μg·(h·L) -1 for pseudoephedrine;(6.8±1.7)h,(1.4 ±0 .4)h ,(2.46±1.88)μg·L -1 and(8.93±6.19)μg·(h·L) -1 for lor a tadine;(15.6±4.7)h,(2.0±1.0)h ,(2.76±1.80)μg·L -1 and(20.63±1 1.33)μg·(h·L) -1 for DCL, respectively. After multiple doses (days 1 to 6 ), the main pharmacokinetics parameters of Cav, DF, and AUCss were (337.4±49.4 )μg·L -1, (0.72±0.28)% and(4 049±594)μg·(h·L) -1 for ps eudoep hedrine; (0.86±0.74)μg·L -1, (3.05±1.37)% and (10.38±8.86)μg·( h·L) -1 for loratadine; (1.31±0.76)μg·L -1, (2.18±0.82)% and (15.69±9.14)μg·(h·L) -1 for DCL, respectively.In conclusion, Loratadine is extensively metabolized in the liver to an active m etabolite(DCL), so first pass has resulted in obvious difference within the vo lunteers. In contrast with the common formulation, this twice-daily combination tablet formulation has showed the character of extended-release. After a singe l dose, t 1/2 and t max of pesudoephedrine have been increase d , and the same time, c max has been reduced. After multiple doses, DF o f pesudoephedrine was little. The time-concentration curve of pesudoephedrine sulfate has two peaks, which wa s the proof of immediate-extended release coating.