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Functional role of P-glycoprotein in limiting intestinal absorption of drugs: contribution of passive permeability to P-glycoprotein mediated efflux transport.
Mol Pharm 2005 Jan-Feb; 2(1):12-21MP

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.

Authors+Show Affiliations

Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Sector No. 67, SAS Nagar 160 062, Punjab, India.No affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

15804173

Citation

Varma, Manthena V S., et al. "Functional Role of P-glycoprotein in Limiting Intestinal Absorption of Drugs: Contribution of Passive Permeability to P-glycoprotein Mediated Efflux Transport." Molecular Pharmaceutics, vol. 2, no. 1, 2005, pp. 12-21.
Varma MV, Sateesh K, Panchagnula R. Functional role of P-glycoprotein in limiting intestinal absorption of drugs: contribution of passive permeability to P-glycoprotein mediated efflux transport. Mol Pharm. 2005;2(1):12-21.
Varma, M. V., Sateesh, K., & Panchagnula, R. (2005). Functional role of P-glycoprotein in limiting intestinal absorption of drugs: contribution of passive permeability to P-glycoprotein mediated efflux transport. Molecular Pharmaceutics, 2(1), pp. 12-21.
Varma MV, Sateesh K, Panchagnula R. Functional Role of P-glycoprotein in Limiting Intestinal Absorption of Drugs: Contribution of Passive Permeability to P-glycoprotein Mediated Efflux Transport. Mol Pharm. 2005;2(1):12-21. PubMed PMID: 15804173.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Functional role of P-glycoprotein in limiting intestinal absorption of drugs: contribution of passive permeability to P-glycoprotein mediated efflux transport. AU - Varma,Manthena V S, AU - Sateesh,Khandavilli, AU - Panchagnula,Ramesh, PY - 2005/4/5/pubmed PY - 2005/5/13/medline PY - 2005/4/5/entrez SP - 12 EP - 21 JF - Molecular pharmaceutics JO - Mol. Pharm. VL - 2 IS - 1 N2 - 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. SN - 1543-8384 UR - https://www.unboundmedicine.com/medline/citation/15804173/Functional_role_of_P_glycoprotein_in_limiting_intestinal_absorption_of_drugs:_contribution_of_passive_permeability_to_P_glycoprotein_mediated_efflux_transport_ L2 - https://dx.doi.org/10.1021/mp0499196 DB - PRIME DP - Unbound Medicine ER -