title: Increased intestinal P-glycoprotein expression and activity with progression of diabetes and its modulation by epigallocatechin-3-gallate: Evidence from pharmacokinetic studies.
abstract: The aim of this study was to evaluate the change in the expression and the activity of intestinal P-glycoprotein (efflux transporter) with progression of diabetes in rats. Diabetes was induced in Wistar rats using a combination of low dose streptozotocin along with high fat diet. The expression of intestinal P-glycoprotein significantly increased (P≤0.05) with the progression of diabetes which was inferred from the mRNA analysis of mdr1a and mdr1b genes in the ileum segment of rat intestine. Furthermore, a significant increase (P≤0.05) in Na(+)-K(+) ATPase activity was observed in the ileum segment of rat intestine with the progression of diabetes. As a result of this, a significant decrease in the intestinal uptake and peroral bioavailability of the P-glycoprotein substrates (verapamil and atorvastatin) was observed along with the progression of diabetes as compared to normal animals. To address this problem of impaired drug uptake and bioavailability, a reported P-glycoprotein inhibitor, epigallocatechin-3-gallate, was experimentally evaluated. The treatment with epigallocatechin-3-gallate resulted in significant reduction in the expression and activity of P-glycoprotein and subsequent improvement in the intestinal uptake and peroral bioavailability of both verapamil and atorvastatin in normal as well as in diabetic animals. The findings of this study rationalised the use and established the mechanism of action of epigallocatechin-3-gallate to overcome P-glycoprotein mediated drug efflux and will also be helpful in therapeutic drug monitoring in diabetes.
authors.affiliation: Department of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, S. G. Highway, Thaltej, Ahmedabad 380054, Gujarat, India.
authors.forename: Ranjeet Prasad
authors.initials: RP
authors.lastname: Dash
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research - Ahmedabad, C/O-B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, S. G. Highway, Thaltej, Ahmedabad 380054, Gujarat, India.
authors.forename: Bhanuchander
authors.initials: B
authors.lastname: Ellendula
authors.affiliation: Department of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, S. G. Highway, Thaltej, Ahmedabad 380054, Gujarat, India.
authors.forename: Milee
authors.initials: M
authors.lastname: Agarwal
authors.affiliation: Department of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, S. G. Highway, Thaltej, Ahmedabad 380054, Gujarat, India. Electronic address: manishnivsarkar@gmail.com.
authors.forename: Manish
authors.initials: M
authors.lastname: Nivsarkar
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000069059:Atorvastatin / Q000493:pharmacokinetics*; D001682:Biological Availability; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D018450:Disease Progression; D007082:Ileum / Q000378:metabolism*; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014700:Verapamil / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002392:Catechin; D000069059:Atorvastatin; C045651:epigallocatechin gallate; D014700:Verapamil; D000254:Sodium-Potassium-Exchanging ATPase
keywords: ATPase; Diabetes; Epigallocatechin-3-gallate; P-glycoprotein; Pharmacokinetics