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Exact kinetic analysis of passive transport across a polarized confluent MDCK cell monolayer modeled as a single barrier
Journal article   Peer reviewed

Exact kinetic analysis of passive transport across a polarized confluent MDCK cell monolayer modeled as a single barrier

Thuy Thanh Tran, Tracy Gales, Beverly Maleeff, Tanya Aldinger, Joseph W. Polli, Andrew Ayrton, Harma Ellens, Joe Bentz and Aditya Mittal
Journal of pharmaceutical sciences, v 93(8), pp 2108-2123
Aug 2004
DOI: https://doi.org/10.1002/jps.20105
PMID: 15236458
Featured in Collection :   UN Sustainable Development Goals @ Drexel

Abstract

amprenavir loperamide MDCKII permeability quinidine
Knowledge of the passive permeability coefficient for new drugs is useful for estimating the fraction absorbed across the gastrointestinal tract. The commonly used approximate formula for the passive permeability coefficient is based on the initial rate of permeation across cell monolayers, requires measurement during the linear phase of permeation, and is not applicable when there is significant back flux of compound or mass balance problem. To develop a rigorous equation that can be used at any time point, i.e., that is valid outside of the linear phase, the mass action equations were integrated for a standard single barrier model of passive permeability. The simple analytical solution found also allows correction for both loss of drug (e.g., due to binding and/or hydrolysis) and sampling volume loss for multiple time point experiments. To test this equation, we measured the passive permeation of three well characterized drugs (amprenavir, quinidine, and loperamide) across confluent monolayers of MDCKII-hMDR1 cells. The potent P-glycoprotein inhibitor GF120918 was used to inhibit P-glycoprotein activity, so only passive permeability was determined. Dramatically different time-dependent behavior was observed for the three compounds, with loperamide showing significant loss of compound, and loperamide and quinidine causing plasma membrane modifications over time. The simple and exact equation for the permeability coefficient developed here works from start of transport to equilibrium, being valid when the commonly used approximate equation may not be. Thus, the exact equation is safer to use in any context, even for single time point estimates in high-throughput permeability assays.

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Collaboration types
Industry collaboration
Domestic collaboration
International collaboration
Web of Science research areas
Chemistry, Medicinal
Chemistry, Multidisciplinary
Pharmacology & Pharmacy
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