Impact of excipients on the absorption of P-glycoprotein substrates in vitro and in vivo.
The efflux transporter, P-glycoprotein (P-gp), located in the apical membranes of intestinal absorptive cells, can reduce the bioavailability of a wide range of orally administered drugs. A number of surfactants/excipients have been shown to inhibit P-gp, and thus potentially enhance drug absorption. In this study, the improved everted gut sac technique was used to screen excipients for their ability to enhance the absorption of digoxin and celiprolol in vitro. The most effective excipients with digoxin were (at 0.5%, w/v): Labrasol > Imwitor 742 > Acconon E = Softigen 767 > Cremophor EL > Miglyol > Solutol HS 15 > Sucrose monolaurate > Polysorbate 20 > TPGS > Polysorbate 80. With celiprolol, Cremophor EL and Acconon E had no effect, but transport was enhanced by Softigen 767 > TPGS > Imwitor 742. In vivo, the excipients changed the pharmacokinetic profile of orally administered digoxin or celiprolol, but without increasing the overall AUC. The most consistent change was an early peak of absorption, probably due to the higher concentration of excipient in the proximal intestine where the expression of P-gp is lower. These studies show that many excipients/surfactants can modify the pharmacokinetics of orally administered drugs that are P-gp substrates.
Cornaire
Gilles
G
Laboratoire de Cinétique des Xénobiotiques, UMR 181 Physiopathologie et Toxicologie Expérimentale (UPTE INRA-ENVT), Faculté des Sciences Pharmaceutiques, 35 chemin des Maraîchers, 31062 Toulouse, France.
Woodley
John
J
Hermann
Philippe
P
Cloarec
Alix
A
Arellano
Cécile
C
Houin
Georges
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000493:pharmacokinetics*; D000818:Animals; D004077:Digoxin / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005079:Excipients / Q000493:pharmacokinetics*; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000032:analysis / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005079:Excipients; D004077:Digoxin; D007770:L-Lactate Dehydrogenase