Variability in In Vitro OATP1B1/1B3 Inhibition Data: Impact of Incubation Conditions on Variability and Subsequent Drug Interaction Predictions.

Autor: McFeely SJ; Department of Pharmaceutics, UW Drug Interaction Solutions, University of Washington, Seattle, Washington, USA., Ritchie TK; Department of Pharmaceutics, UW Drug Interaction Solutions, University of Washington, Seattle, Washington, USA., Ragueneau-Majlessi I; Department of Pharmaceutics, UW Drug Interaction Solutions, University of Washington, Seattle, Washington, USA.
Jazyk: angličtina
Zdroj: Clinical and translational science [Clin Transl Sci] 2020 Jan; Vol. 13 (1), pp. 47-52. Date of Electronic Publication: 2019 Sep 28.
DOI: 10.1111/cts.12691
Abstrakt: As the research into the organic anion transporting polypeptides (OATPs) continues to grow, it is important to ensure that the data generated are accurate and reproducible. In the in vitro evaluation of OATP1B1/1B3 inhibition, there are many variables that can contribute to variability in the resulting inhibition constants, which can then, in turn, contribute to variable results when clinical predictions (R-values) are performed. Currently, the only experimental condition recommended by the US Food and Drug Administration (FDA) is the inclusion of a pre-incubation period. 1 To identify other potential sources of variability, a descriptive analysis of available in vitro inhibition data was completed. For each of the 21 substrate/inhibitor pairs evaluated, cell type and pre-incubation were found to have the greatest effect on half-maximal inhibitory concentration (IC 50 ) variability. Indeed, when only HEK293 cells and co-incubation conditions were included, the observed variability for the entire data set (highest IC 50 /lowest) was reduced from 12.4 to 5.2. The choice of probe substrate used in the study also had a significant effect on inhibitor constant variability. Interestingly, despite the broad range of inhibitory constants identified, these two factors showed little effect on the calculated R-values relative to the FDA evaluation cutoff of 1.1 triggering a clinical evaluation for the inhibitors evaluated. However, because of the small data set available, further research is needed to confirm these preliminary results and define best practice for the study of OATPs.
(© 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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