Active Secretion of Drugs from the Small Intestinal Epithelium in Rats by P-Glycoprotein Functioning as an Absorption Barrier

Abstract

Because the significance of P-glycoprotein in the in-vivo secretion of beta-blockers in intestinal epithelial cells is unclear, the secretory mechanism for beta-blockers and other drugs has been evaluated. Uptake of the beta-blockers acebutolol, celiprolol, nadolol and timolol, and the antiarrhythmic agent, quinidine by the multidrug-resistant leukaemic cell line variant K562/ADM was significantly lower than that by drug-sensitive K562 cells, suggesting that these beta-blockers are transported by P-glycoprotein out of cells. The reduced uptake of acebutolol by the drug-resistant K562/ADM cells was reversed by treating the cells with anti-P-glycoprotein monoclonal antibody, MRK16, whereas no such alteration in uptake was observed for drug-sensitive K562 cells. Acebutolol uptake by K562/ADM cells was, moreover, markedly enhanced, in a concentration-dependent manner, in the presence of the specific P-glycoprotein inhibitors, MS-209 and cyclosporin. Caco-2 cells were used for evaluation of the role of P-glycoprotein in intestinal permeability to drugs in-vitro. Basolateral-to-apical transport of acebutolol was twice that in the reverse direction. A similar polarized flux was also observed in the transport of vinblastine, but not in that of acetamide or mannitol. When in-vivo intestinal absorption was evaluated by the rat jejunal loop method, with simultaneous intravenous administration of a P-glycoprotein inhibitor, cyclosporin, intestinal absorption of both acebutolol and vinblastine increased 2.6- and 2.2-fold, respectively, but no such enhancement was observed in the absorption of acetamide. The effect of cyclosporin on the intestinal absorption of several drugs was further examined, and the extent of the contribution of P-glycoprotein as an absorption barrier to those drugs was evaluated. ATP depletion by occlusion of the superior mesenteric artery resulted in a clear increase in epithelial permeability to vinblastine, but not to 3-O-methylglucose or acetamide, indicating that vinblastine is secreted by ATP-dependent P-glycoprotein into the lumen. These findings demonstrate that P-glycoprotein plays a role as an absorption barrier by transporting several drugs from intestinal cells into the lumen.

Modulation of P-glycoprotein activity in Calu-3 cells using steroids and β-ligands

“…The cardioselective β-blockers acebutolol, celiprolol and talinolol, have been shown to exhibit Pgp-mediated secretion in intestinal Caco-2 cells (Karlsson et al, 1993;Terao et al, 1996;Hilgendorf et al, 2000). Propranolol uptake was reported to be increased by several Pgp ligands including cyclosporin A, progesterone and Rh123, in conjuctival epithelium (Yang et al, 2000).…”

A polymorphism C3435T of the MDR-1 gene associated with smoking or high body mass index increases the risk of sporadic breast cancer in women

“…This protein is encoded by the MDR-1 gene located on human chromosome 7 at q21.1 (21) and belongs to a large group of transport proteins, known as the ATP-binding cassette (ABC) superfamily (22). P-glycoprotein is highly expressed in apical membranes of organs with excretory function, such as liver, small intestine or kidney (23)(24)(25), where it mediates the excretion of xenobiotics into the bile, urine and gut lumen. In addition, high expression was found in endothelial cells of the central nervous system (26) and breast carcinoma (27).…”

Involvement of Multidrug Resistance-Associated Protein 1 in Intestinal Toxicity of Methotrexate

“…play a key role in drug absorption (7,8,(13)(14)(15)(16), little is known about the pharmacological and/or toxicological effects of transporter(s) expressed in undifferentiated cells in the small intestine. The aim of the present study is to clarify whether Mrp1, which was reported to be expressed in proliferative cells of crypts in mice, is involved in the intestinal toxicity provoked by MTX in vivo.…”

“…For example, P-glycoprotein (P-gp/ABCB1) and Mrp2 limit the oral bioavailability of certain ß-blockers and new quinolone antibiotics by extruding these drugs into the intestinal tract (13,14). Both Mrp2 and Mrp3/Abcc3 are expressed in the small intestine, and accept MTX as a substrate (15,16).…”