title: Impact of P-glycoprotein-mediated intestinal efflux kinetics on oral bioavailability of P-glycoprotein substrates.
abstract: Studies of many P-glycoprotein (Pgp) substrates have demonstrated a significant effect of Pgp-mediated efflux on intestinal drug transport. However, most of these studies were designed to detect whether a particular drug is a Pgp substrate and thus were conducted at very low concentrations. We performed two simulations to evaluate the effect of Pgp-mediated efflux on oral drug absorption at various concentrations. In the first simulation, a steady-state model allowed us to predict whether the contribution of Pgp to oral drug absorption would be significant at clinically relevant concentrations. Our second simulation investigated the role of Pgp-mediated efflux in oral absorption with a dynamic compartmental absorption and transit model linked to a pharmacokinetic model. For high-solubility drugs, Pgp-mediated efflux altered the bioavailability only at drug concentrations corresponding to doses much lower than the usual clinical dose. The ratio of transporter-mediated transport to passive transport determined whether intestinal Pgp transporters would reduce the bioavailability of high-solubility drugs.
authors: Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20855, USA.
authors: Hyojong
authors: H
authors: Kwon
authors: Robert A
authors: RA
authors: Lionberger
authors: Lawrence X
authors: LX
authors: Yu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D001682:Biological Availability; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D010599:Pharmacokinetics; D012995:Solubility; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations