Functional role of P-glycoprotein in limiting intestinal absorption of drugs: contribution of passive permeability to P-glycoprotein mediated efflux transport

Mol Pharm. Jan-Feb 2005;2(1):12-21. doi: 10.1021/mp0499196.

Abstract

The aim of the present study is to evaluate the quantitative contribution of passive permeability to P-glycoprotein-mediated (P-gp-mediated) efflux and the functional activity of P-gp in determining intestinal absorption of drugs, and demonstrate the relationship between efflux parameters and intestinal permeability. MDRI-MDCKII cell monolayer permeability, human intestinal absorption (HIA), and solubility data were systematically collected from the literature. Drugs were classified as a total of 63 P-gp substrates (P-gpS) and 73 nonsubstrates (NS) on the basis of efflux ratio or calcein AM inhibition and ATPase activity assays. Efflux parameters, efflux ratio (ER) and absorption quotient (AQ), were correlated to the monolayer permeability. MDRI-MDCKII cell monolayer permeability characteristics were found to be distinctly different between P-gpS and NS datasets. The ER for P-gpS was found to increase with absorptive permeability until 20 nm.s(-1), but reduced for P-gpS with high absorptive permeability. The AQ showed a linear inverse relationship with absorptive permeability. Overall, efflux parameters, ER and AQ, indicated that the transport of P-gpS with moderate passive permeability is highly attenuated by P-gp, while passive permeability overrules the P-gp-mediated efflux for high-permeability molecules. Most of the P-gpS were found towards the upper limits of molecular weight (>500) and calculated total polar surface area (>75 A(2)). This dataset indicated that unfavorable chemical features of P-gpS limit passive permeability and thus are more susceptible to P-gp-mediated efflux. In conclusion, passive permeability versus P-gp-mediated efflux determines intestinal permeability of P-gpS, where P-gp limits absorption of only moderately permeable compounds. Thus, integrating these factors with drug characteristics of the Biopharmaceutics Classification System (BCS) class better predicts the functional role of P-gp in limiting intestinal drug absorption.

Publication types

  • Comparative Study

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily B / pharmacokinetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / pharmacokinetics*
  • Adenosine Triphosphatases / analysis
  • Adenosine Triphosphatases / metabolism
  • Animals
  • Biological Availability
  • Biological Transport
  • Cell Line
  • Cell Membrane Permeability / drug effects*
  • Dogs
  • Fluoresceins / metabolism
  • Humans
  • Intestinal Absorption*
  • Pharmaceutical Preparations / metabolism*
  • Predictive Value of Tests
  • Solubility

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Fluoresceins
  • Pharmaceutical Preparations
  • calcein AM
  • Adenosine Triphosphatases