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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 (F_ic) as the fraction of extracellular drug available to bind intracellular targets, and we assess how F_ic is 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 F_ic of its substrates, while P-gp decreased F_ic. 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 F_ic was up to 35-fold lower in the configuration with high expression of drug-eliminating transporters and enzymes. We conclude that F_ic provides 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).

SUBMITTER: Mateus A

PROVIDER: S-EPMC5320532 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Intracellular drug bioavailability: a new predictor of system dependent drug disposition.

Mateus André A Treyer Andrea A Wegler Christine C Karlgren Maria M Matsson Pär P Artursson Per P

Scientific reports 20170222

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 (F<sub>ic</sub>) as the fraction of extracellular drug available to bind intracellular targets, and we assess how F<sub>ic</sub> is affected by cellular drug disposition processes. We first investigated the impact of two essential drug transporters separately, one influx transporter (OATP1B1; SLC ...[more]

PMID: 28225057

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Dataset Information

Intracellular drug bioavailability: a new predictor of system dependent drug disposition.

Publications

Intracellular drug bioavailability: a new predictor of system dependent drug disposition.

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