Impact of transporters in oral absorption: a case study of in vitro and in vivo organic anion absorption.
A key determinant for oral bioavailability of a drug candidate is the intestinal epithelial permeation of the drug candidate. This intestinal permeation may be affected by interactions on membrane transporters expressed in the intestinal epithelial cells. The purpose of the present study was to investigate whether transporters were involved in the intestinal absorption of an organic anion A275 and to compare the impact of interactions related to transporters in the Caco-2 cell model versus the in vivo rat model of intestinal absorption. In both models, it was investigated whether intestinal permeation of A275 was concentration dependent and affected by inhibitors or competitive organic anions. Interactions related to transporters in intestinal permeation was clearly demonstrated in the Caco-2 cell model but was not directly evident for in vivo rat absorption. However, an observed biphasic in vivo absorption and a large intervariability between rats might mask a dose-dependent absorption of A275. To avoid these suggested interactions, a dose of at least 10 mg/kg, which saturates the intestinal transporters involved in A275 absorption, should be administered, but at doses below that the risk of such drug interactions should be taken into account.
Gram
Luise K
LK
Molecular Biopharmaceutics, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Copenhagen, Denmark.
Rist
Gerda Marie
GM
Steffansen
Bente
B
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000502:physiology*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; C450859:SLCO2B1 protein, human; C476575:organic solute transporter alpha, human; C476577:SLC51B protein, human