Michiels M, Monbaliu J, Hendriks R, Geerts R, Woestenborghs R, Heykants J
Department of Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutica Research Laboratories, Beerse, Belgium.
Arzneimittelforschung. 1987 Oct;37(10):1159-67.
The plasma kinetics and tissue distribution of the gastrokinetic (+/-)-cis-4-amino-5-chloro-N-[1-(3-(4-fluorophenoxy)propyl]-3-methoxy-4- piperidinyl]-2-methoxybenzamide monohydrate (cisapride, R 51 619) have been studied in the rat, rabbit and dog. After intravenous administration to rats (5 mg/kg) and dogs (0.63 mg/kg) plasma level-time curves were adequately fitted to a two-compartmental model. The plasma clearance (ClT) and volume of distribution (Vdss) averaged 91 ml/min.kg and 4.7 l/kg in the rat and 4.2 ml/min.kg and 0.82 l/kg in the dog, respectively. Following oral administration, cisapride was rapidly and almost completely absorbed from the gastrointestinal tract in rats and rabbits. The absorption was somewhat slower in the dog. In male rats the plasma radioactivity was mainly due to metabolites, unaltered cisapride representing on average 10% of the total radioactivity. A markedly larger proportion of the parent drug was seen in female rats. Linear plasma kinetics were observed for cisapride in the dose range of 10 to 160 mg/kg. Similarly in the dog, linearity was observed after oral administration in the range of 0.31 to 10 mg/kg. The plasma kinetics remained unaltered on repeated oral doses of 10 mg/kg to rats and subchronic intravenous administration at 0.63 mg/kg to dogs. Compared with intravenous administration, the absolute bioavailability of oral cisapride was 23% in rats and 53% in the dog for the drug given in solution. The terminal plasma half-life of cisapride was about 1-2 h in the rat and about 4-10 h in the rabbit and dog.(ABSTRACT TRUNCATED AT 250 WORDS)
已在大鼠、兔和犬中研究了促胃肠动力药（±）-顺式-4-氨基-5-氯-N-[1-(3-(4-氟苯氧基)丙基]-3-甲氧基-4-哌啶基]-2-甲氧基苯甲酰胺一水合物（西沙必利，R 51 619）的血浆动力学和组织分布。给大鼠（5 mg/kg）和犬（0.63 mg/kg）静脉给药后，血浆浓度-时间曲线能很好地拟合二室模型。大鼠的血浆清除率（ClT）和稳态分布容积（Vdss）平均分别为91 ml/min·kg和4.7 l/kg，犬分别为4.2 ml/min·kg和0.82 l/kg。口服给药后，西沙必利在大鼠和兔中迅速且几乎完全从胃肠道吸收。犬的吸收稍慢。在雄性大鼠中，血浆放射性主要归因于代谢产物，未改变的西沙必利平均占总放射性的10%。在雌性大鼠中可见明显更大比例的母体药物。在10至160 mg/kg剂量范围内，西沙必利呈现线性血浆动力学。同样在犬中，口服给药在0.31至10 mg/kg范围内呈现线性。对大鼠重复口服10 mg/kg剂量以及对犬以0.63 mg/kg进行亚慢性静脉给药后，血浆动力学保持不变。与静脉给药相比，口服西沙必利溶液时，大鼠的绝对生物利用度为23%，犬为53%。西沙必利的终末血浆半衰期在大鼠中约为1 - 2小时，在兔和犬中约为4 - 10小时。（摘要截断于250字）
