Membrane transport of camptothecin: facilitation by human P-glycoprotein (ABCB1) and multidrug resistance protein 2 (ABC
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BioMed Central
Open Access
Research article
Membrane transport of camptothecin: facilitation by human P-glycoprotein (ABCB1) and multidrug resistance protein 2 (ABCC2) Anita K Lalloo1, Feng R Luo1,3, Ailan Guo1,4, Pankaj V Paranjpe1, SungHack Lee1, Viral Vyas2, Eric Rubin2 and Patrick J Sinko*1,2 Address: 1Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA, 2The Cancer Institute of New Jersey, New Brunswick, New Jersey, USA, 3Bristol Myers Squibb Co., Princeton, New Jersey, USA and 4Hoffmann-La Roche, Department of Discovery Pharmacology, Nutley, New Jersey, USA Email: Anita K Lalloo - [email protected]; Feng R Luo - [email protected]; Ailan Guo - [email protected]; Pankaj V Paranjpe - [email protected]; Sung-Hack Lee - [email protected]; Viral Vyas - [email protected]; Eric Rubin - [email protected]; Patrick J Sinko* - [email protected] * Corresponding author
Published: 04 May 2004 BMC Medicine 2004, 2:16
Received: 02 December 2003 Accepted: 04 May 2004
This article is available from: http://www.biomedcentral.com/1741-7015/2/16 © 2004 Lalloo et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
Caco-2 cellscamptothecineffluxMDCK II cellsMultidrug Resistance Protein 2membrane transportP-glycoproteinsecretion
Abstract Background: The purpose of the present study was to continue the investigation of the membrane transport mechanisms of 20-(S)-camptothecin (CPT) in order to understand the possible role of membrane transporters on its oral bioavailability and disposition. Methods: The intestinal transport kinetics of CPT were characterized using Caco-2 cells, MDCKII wild-type cells and MDCKII cells transfected with human P-glycoprotein (PGP) (ABCB1) or human multidrug resistance protein 2 (MRP2) (ABCC2). The effects of drug concentration, inhibitors and temperature on CPT directional permeability were determined. Results: The absorptive (apical to basolateral) and secretory (basolateral to apical) permeabilities of CPT were found to be saturable. Reduced secretory CPT permeabilities with decreasing temperatures suggests the involvement of an active, transporter-mediated secretory pathway. In the presence of etoposide, the CPT secretory permeability decreased 25.6%. However, inhibition was greater in the presence of PGP and of the breast cancer resistant protein inhibitor, GF120918 (52.5%). The involvement of additional secretory transporters was suggested since the basolateral to apical permeability of CPT was not further reduced in the presence of increasing concentrations of GF120918. To investigate the involvement of specific apically-located secretory membrane transporters, CPT transport studies were conducted using MDCKII/PGP cells and MDCKII/MRP2 cells. CPT carrier-mediated permeability was approximately twofold g
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