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Impact of P-Glycoprotein-Mediated Intestinal Efflux Kinetics on Oral Bioavailability of P-Glycoprotein Substrates

2004; American Chemical Society; Volume: 1; Issue: 6 Linguagem: Inglês

10.1021/mp049921x

1543-8392

Hyojong Kwon, Robert Lionberger, Lawrence X. Yu,

Antibiotics Pharmacokinetics and Efficacy

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.