Potential roles of P-gp and calcium channels in loperamide and diphenoxylate transport.
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.
Crowe
Andrew
A
School of Pharmacy, Curtin University of Technology, GPO Box U1987, Perth, Western Australia, 6845, Australia. A.P.Crowe@curtin.edu.au
Wong
Penny
P
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
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