Functional Role of P-Glycoprotein in Limiting Intestinal Absorption of Drugs:  Contribution of Passive Permeability to P-Glycoprotein Mediated Efflux Transport

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.

Physicochemical Property Space of Hepatobiliary Transport and Computational Models for Predicting Rat Biliary Excretion

“…The apparent molecular mass cutoff noted for BE may indicate that the potential substrate specificity of the transporters involved in hepatobiliary transport is associated with molecular mass. The fact that canalicular efflux transporters have a much wider substrate specificity implies that the secretion across canalicular membrane is not selective to a certain molecular size (Varma et al, 2005(Varma et al, , 2010aAller et al, 2009;Gandhi and Morris, 2009;Matsson et al, 2009). However, our analysis using a sizable dataset showed that hOATP and rOatp1b2 substrates tend toward large molecular mass ( Fig.…”

Transport of Selected PET Radiotracers by Human P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2): An In Vitro Screening

“…Some of the compounds we have tested have been evaluated in conventional bidirectional transport studies. These studies showed that verapamil is a poorer P-gp substrate (efflux ratio of 1.7) than loperamide (efflux ratio of 9.9) (20,38). They also revealed that deprenyl and flumazenil are not P-gp substrates.…”

In Vitro to In Vivo Comparison of the Substrate Characteristics of Sorafenib Tosylate toward P-Glycoprotein

“…(therapeutic dose), the P-gp-mediated transport of sorafenib in patients might be saturated. Compared with digoxin, vinblastine (Table 2), and paclitaxel (efflux ratio of 108) (Varma et al, 2005), for which an in vivo effect of P-gp on the pharmacokinetics has been shown (Schinkel et al, 1994(Schinkel et al, , 1995van Asperen et al, 1998), sorafenib showed a lower efflux ratio in L-MDR1 cells. Summarizing the in vitro findings, with regard to its efflux ratio sorafenib is classified as a weak P-gp substrate.…”