title: Study on in situ and in vivo absorption kinetics of phenytoin by modulating P-glycoprotein with verapamil in rats.
abstract: 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.
authors.affiliation: DMPK and Clinical Pharmacology Division, Department of Pharmacology, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, AP, India. prasadneerati@gmail.com
authors.forename: Prasad
authors.initials: P
authors.lastname: Neerati
authors.forename: Dinesh
authors.initials: D
authors.lastname: Ganji
authors.forename: Sathish Kumar
authors.initials: SK
authors.lastname: Bedada
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D007082:Ileum / Q000378:metabolism*; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D010477:Perfusion; D010539:Permeability; D010672:Phenytoin / Q000097:blood / Q000493:pharmacokinetics*; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D010672:Phenytoin; D011433:Propranolol; D014700:Verapamil