title: Potential roles of P-gp and calcium channels in loperamide and diphenoxylate transport.
abstract: This study examined the accumulation and transport of two related systemic opioids used as antidiarrhoeal drugs and compared their rates of transport with known P-glycoprotein (P-gp) substrates used in our in vitro environment. Cellular uptake and efflux and transcellular transport were all determined using Caco-2 cells after exposure to loperamide or diphenoxylate, with or without a range of efflux inhibitors. Bidirectional transport studies of 5 microM loperamide showed efflux to be fivefold higher than influx (42 x 10(-6) compared to 8 x 10(-6) cm/s); however, this decreased to twofold at 10 microM and was abolished using 100 microM loperamide. An uptake pathway was also discovered when P-gp was inhibited which, in the presence of Ca(2+) channel blockers, was amplified, providing a potential mechanism for central nervous system effects to be increased upon blockage of L-type calcium channels, quite separate from any P-gp inhibition. Diphenoxylate transport, however, showed little sign of P-gp-mediated efflux. Diphenoxylate accumulated readily within cells, yet transport through cells was very low. Additionally, efflux inhibitors had little impact on transport or accumulation, suggesting that diphenoxylate was not a substrate for an efflux mechanism.
authors: School of Pharmacy, Curtin University of Technology, GPO Box U1987, Perth, Western Australia, 6845, Australia. A.P.Crowe@curtin.edu.au
authors: Andrew
authors: A
authors: Crowe
authors: Penny
authors: P
authors: Wong
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000930:Antidiarrheals / Q000493:pharmacokinetics*; D001692:Biological Transport; D018938:Caco-2 Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology; D004157:Diphenoxylate / Q000493:pharmacokinetics*; D004347:Drug Interactions; D006801:Humans; D008139:Loperamide / Q000493:pharmacokinetics*; D009294:Narcotics / Q000493:pharmacokinetics*; D011339:Probenecid / Q000494:pharmacology; D013442:Sulfinpyrazone / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000930:Antidiarrheals; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D003524:Cyclosporins; D009294:Narcotics; D008139:Loperamide; D004157:Diphenoxylate; D016572:Cyclosporine; D014700:Verapamil; D011339:Probenecid; C070272:valspodar; D013442:Sulfinpyrazone