title: The effects of PLGA microparticles on intestinal absorption of p-glycoprotein substrate using the everted rat intestinal sac model.
abstract: In addition to the effects of physical processes (solubility, tissue permeability, and formulation factors), p-glycoprotein (P-gp) efflux across the apical membrane of enterocytes can affect the rate and amount of compound diffusing across the basolateral membrane of the intestine and entering the blood stream. The first objective was the evaluation of a possible role of intestinal P-gp in the kinetic absorption of a model drug: furosemide. To achieve this goal, two series of transport experiments, apical to basolateral (A → B) and basolateral to apical (B → A) with and without verapamil -a known P-gp inhibitor- were performed. The second objective was to evaluate whether encapsulation into polymeric microparticles might improve the oral absorption of a poorly permeable drug. Thus, spherical poly lactic-glycolic acid (PLGA) microparticles of furosemide were designed, and the concentration of transported drug was evaluated using an in situ everted rat gut sac model. The results indicated that verapamil at various drug concentrations (5-100 μg/mL) significantly decreased the B → A (2-3 fold) and increased the A → B (1.5-2 fold) permeability of furosemide, which showed that this drug could be a P-gp substrate. We found that encapsulation of furosemide in PLGA microparticles can markedly increase (2-4 fold) intestinal absorption of drug even higher than verapamil does. We conclude that biodegradable microparticles are a promising strategy to increase the bioavailability of drugs and have advantages compared to P-gp inhibitors with pharmacological and severe side effects at doses required for efflux pump inhibition.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Kermanshah University of Medical Sciences, 67145-1673, Kermanshah, Iran. kderakhshandeh@kums.ac.ir
authors.forename: Katayoun
authors.initials: K
authors.lastname: Derakhshandeh
authors.forename: Aidin
authors.initials: A
authors.lastname: Hosseinalizadeh
authors.forename: Maryam
authors.initials: M
authors.lastname: Nikmohammadi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D055598:Chemical Phenomena; D004232:Diuretics / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism*; D004339:Drug Compounding; D005665:Furosemide / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology; D008863:Microspheres; D009994:Osmolar Concentration; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004232:Diuretics; D004337:Drug Carriers; D049990:Membrane Transport Modulators; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D005665:Furosemide