title: Intracellular drug bioavailability: a new predictor of system dependent drug disposition.
abstract: Intracellular drug exposure is influenced by cell- and tissue-dependent expression of drug-transporting proteins and metabolizing enzymes. Here, we introduce the concept of intracellular bioavailability (Fic) as the fraction of extracellular drug available to bind intracellular targets, and we assess how Ficis affected by cellular drug disposition processes. We first investigated the impact of two essential drug transporters separately, one influx transporter (OATP1B1; SLCO1B1) and one efflux transporter (P-gp; ABCB1), in cells overexpressing these proteins. We showed that OATP1B1 increased Ficof its substrates, while P-gp decreased Fic. We then investigated the impact of the concerted action of multiple transporters and metabolizing enzymes in freshly-isolated human hepatocytes in culture configurations with different levels of expression and activity of these proteins. We observed that Ficwas up to 35-fold lower in the configuration with high expression of drug-eliminating transporters and enzymes. We conclude that Ficprovides a measurement of the net impact of all cellular drug disposition processes on intracellular bioavailable drug levels. Importantly, no prior knowledge of the involved drug distribution pathways is required, allowing for high-throughput determination of drug access to intracellular targets in highly defined cell systems (e.g., single-transporter transfectants) or in complex ones (including primary human cells).
authors.affiliation: Department of Pharmacy, Uppsala University, BMC, Box 580, Uppsala SE-751 23, Sweden.
authors.forename: André
authors.initials: A
authors.lastname: Mateus
authors.affiliation: Department of Pharmacy, Uppsala University, BMC, Box 580, Uppsala SE-751 23, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Treyer
authors.affiliation: Department of Pharmacy, Uppsala University, BMC, Box 580, Uppsala SE-751 23, Sweden.|Cardiovascular and Metabolic Diseases Innovative Medicines, DMPK, AstraZeneca R&D, Mölndal SE-431 83, Sweden.
authors.forename: Christine
authors.initials: C
authors.lastname: Wegler
authors.affiliation: Department of Pharmacy, Uppsala University, BMC, Box 580, Uppsala SE-751 23, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Karlgren
authors.affiliation: Department of Pharmacy, Uppsala University, BMC, Box 580, Uppsala SE-751 23, Sweden.
authors.forename: Pär
authors.initials: P
authors.lastname: Matsson
authors.affiliation: Department of Pharmacy, Uppsala University, BMC, Box 580, Uppsala SE-751 23, Sweden.|Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Uppsala University, Box 580, Uppsala SE-751 23, Sweden.|Science for Life Laboratory Drug Discovery and Development platform (SciLifelab DDD-P), Uppsala University, Uppsala SE-751 23, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Artursson
mesh_terms: D001682:Biological Availability; D002478:Cells, Cultured; D003593:Cytoplasm / Q000737:chemistry*; D022781:Hepatocytes / Q000201:enzymology* / Q000378:metabolism*; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics
chemical_list: D026901:Membrane Transport Proteins; D004364:Pharmaceutical Preparations