DMPK and Clinical Pharmacology Division, Department of Pharmacology, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, AP, India.
Eur J Pharm Sci. 2011 Sep 18;44(1-2):27-31. doi: 10.1016/j.ejps.2011.05.005. Epub 2011 May 27.
P-gp is playing significant role in the development of the drug resistance by altering the absorption of drugs. The objective of present investigation was to study the effect of verapamil on the pharmacokinetics of phenytoin in order to evaluate the role of P-glycoprotein (P-gp) in phenytoin absorption. An in situ single pass intestinal perfusion study was carried out to determine the effect of verapamil on the functional status of intestinal P-gp. Phenytoin (30μM) and propranolol (100μM) co-perfused with and without verapamil (200μM) in rat's ileum. An in vivo study, verapamil (25mg/kg, per oral) was administered 2h before phenytoin (30mg/kg, per oral) dosing in male Wistar rats. Plasma samples were collected at 0, 1, 2, 3, 4, 5, 6, 8, 12 and 24h time points from control and treated animals to determine phenytoin concentrations. An in situ single pass intestinal perfusion study indicated phenytoin to be a P-gp substrate and the function of intestinal P-gp was significantly inhibited in presence of verapamil. After per oral phenytoin dosing, the mean area under the plasma concentration-time curve (AUC) was found to be 35.03±1.83hμg/ml which was increased significantly, i.e. 62.33±2.49hμg/ml (P<0.001) when verapamil was co-administered. Similarly the mean maximum plasma concentration of phenytoin increased from 3.2±0.148μg/ml without verapamil to 6.983±0.272μg/ml (P<0.001) with verapamil. These results are quite stimulating for further development of a clinically useful oral formulation of phenytoin based on P-gp inhibition.
P-糖蛋白通过改变药物的吸收在药物耐药性的发展中起着重要作用。本研究的目的是研究维拉帕米对苯妥英的药代动力学的影响，以评估 P-糖蛋白（P-gp）在苯妥英吸收中的作用。进行了原位单次肠灌流研究，以确定维拉帕米对肠 P-gp 功能状态的影响。在大鼠回肠中，同时或不与维拉帕米（200μM）共灌注苯妥英（30μM）和普萘洛尔（100μM）。在雄性 Wistar 大鼠中，在给予苯妥英（30mg/kg，口服）前 2 小时给予维拉帕米（25mg/kg，口服）进行体内研究。从对照和处理动物中采集 0、1、2、3、4、5、6、8、12 和 24 小时的血浆样本，以确定苯妥英浓度。原位单次肠灌流研究表明，苯妥英是 P-gp 的底物，维拉帕米存在时，肠 P-gp 的功能明显受到抑制。口服给予苯妥英后，发现血浆浓度-时间曲线下面积（AUC）的平均值为 35.03±1.83hμg/ml，当维拉帕米同时给予时，AUC 显著增加，即 62.33±2.49hμg/ml（P<0.001）。同样，苯妥英的最大血浆浓度从无维拉帕米时的 3.2±0.148μg/ml 增加到有维拉帕米时的 6.983±0.272μg/ml（P<0.001）。这些结果对于进一步开发基于 P-gp 抑制的苯妥英临床有用的口服制剂非常有意义。
