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Measurement of Transcellular Transport Rates and Intracellular Drug Sequestration in the Presence of an Extracellular Concentration Gradient

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Quantitative Analysis of Cellular Drug Transport, Disposition, and Delivery

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

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Abstract

In order for a drug to be effective and ultimately successful, it must first gain access to its molecular target at a desired site of action. Conventionally, for the purpose of high-throughput screening of drug candidates during the earliest stages of drug development, transport assays are performed with commercially available, in vitro cell cultures as experimental models. Based on theoretical, physiologically based pharmacokinetics principles, the quantitative measurements obtained with these assays are used to predict drug absorption, distribution, and elimination within the organism. Transcellular drug permeability coefficients, transcellular transport rates, and intracellular drug accumulation can be simultaneously measured using adherent cells grown on porous membrane supports. These measurements are used to elucidate the molecular mechanisms that mediate the transport pathways across epithelial, endothelial, and other cell monolayers, which function to determine drug absorption and distribution within the living organism. In this chapter, we describe the most typical, routine procedures used for measuring the transcellular transport rates and intracellular accumulation of small molecular drugs, in the presence of a drug concentration gradient across a cell monolayer. We will highlight various in vitro cell models that are used to represent different cell barriers in the body. Finally, we will discuss the factors that can cause variations in these experimental measurements and their interpretation, along with the theoretical aspects related to the transcellular transport phenomena driven by extracellular concentration gradients. Therefore, this chapter provides a comprehensive introduction to the quantitative analysis of cellular drug transport, targeting, and disposition. It will serve as a guide to choose the most appropriate in vitro cell culture models, to assist with the interpretation of the data obtained through these experiments, and to outline knowledge gaps and areas of improvement that will be further discussed in the subsequent chapters.

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Acknowledgments

This work was partly supported by grants to KAM from the National Research Foundation of Korea (NRF) funded by the Korea government, Ministry of Science and ICT (MSIT) (NRF-2017R1C1B5015491) and the Ministry of Education (NRF-2018R1D1A1B07048818) and to GRR from the United States National Institutes of Health (R01GM127787-01A1).

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Authors and Affiliations

  1. College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Gyeongnam, Republic of Korea

    Kyoung Ah Min

  2. Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, MI, USA

    Gus R. Rosania

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  1. Kyoung Ah Min
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Correspondence to Kyoung Ah Min or Gus R. Rosania .

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Editors and Affiliations

  1. College of Pharmacy, University of Michigan, Ann Arbor, MI, USA

    Gus R. Rosania

  2. Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA

    Greg M. Thurber

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Min, K.A., Rosania, G.R. (2021). Measurement of Transcellular Transport Rates and Intracellular Drug Sequestration in the Presence of an Extracellular Concentration Gradient. In: Rosania, G.R., Thurber, G.M. (eds) Quantitative Analysis of Cellular Drug Transport, Disposition, and Delivery. Methods in Pharmacology and Toxicology. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1250-7_1

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