Efficacy of novel P-glycoprotein inhibitors to increase the oral uptake of paclitaxel in mice.
P-glycoprotein inhibitors can increase the oral bioavailability of paclitaxel. We have now explored the mechanisms that determine the efficacy of several novel P-glycoprotein inhibitors to increase the absorption of paclitaxel from the gut lumen of mice in both in vivo and in vitro experiments. The inhibitors studied were cyclosporin A, PSC 833, GF120918, LY335979 and R101933. Mass balance studies showed that GF120918 was the most effective inhibitor, resulting in almost complete uptake of paclitaxel. PSC 833 was slightly less effective, whereas cyclosporin A and LY335979 were moderately effective. R101933 had only marginal effects. These findings were in line with in vitro transport experiments using LLC-mdr1a cells. By studying the intra-intestinal kinetics of the agents we found that cyclosporin A, PSC 833 and GF120918 rapidly passed the stomach and traveled concurrently with paclitaxel through the intestines, whereas LY335979 and R101933 delayed stomach emptying. Moreover, these latter compounds appear to be more readily absorbed when released into the intestines thus reducing local intestinal concentrations. Due to their combined effects on absorption and metabolic elimination of paclitaxel, cyclosporin A and PSC 833 resulted in the highest paclitaxel levels in plasma. In conclusion, our models provide insight into the factors that determine the suitability of P-glycoprotein inhibitors to enable oral paclitaxel therapy and will be useful in selecting candidate inhibitors for clinical testing.
Bardelmeijer
Heleen A
HA
Department of Clinical Chemistry, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Ouwehand
Mariët
M
Beijnen
Jos H
JH
Schellens
Jan H M
JH
van Tellingen
Olaf
O
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000166:Acridines / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001552:Benzazepines / Q000494:pharmacology; D001682:Biological Availability; D001693:Biological Transport, Active; D016572:Cyclosporine / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D017239:Paclitaxel / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011804:Quinolines / Q000494:pharmacology; D013270:Stomach / Q000187:drug effects; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000972:Antineoplastic Agents, Phytogenic; D001552:Benzazepines; D003524:Cyclosporins; D003986:Dibenzocycloheptenes; D011804:Quinolines; D044005:Tetrahydroisoquinolines; C095179:zosuquidar trihydrochloride; D016572:Cyclosporine; C411474:laniquidar; C083501:Elacridar; D017239:Paclitaxel; C070272:valspodar