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Impact of Intracellular Concentrations on Metabolic Drug-Drug Interaction Studies
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0002-4533-7761
Roche Innovat Ctr Basel, Roche Pharmaceut Res & Early Dev, Basel, Switzerland.
Roche Innovat Ctr Basel, Roche Pharmaceut Res & Early Dev, Basel, Switzerland.
Roche Innovat Ctr Basel, Roche Pharmaceut Res & Early Dev, Basel, Switzerland.
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2019 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 21, no 5, article id 77Article in journal (Refereed) Published
Abstract [en]

Accurate prediction of drug-drug interactions (DDI) is a challenging task in drug discovery and development. It requires determination of enzyme inhibition in vitro which is highly system-dependent for many compounds. The aim of this study was to investigate whether the determination of intracellular unbound concentrations in primary human hepatocytes can be used to bridge discrepancies between results obtained using human liver microsomes and hepatocytes. Specifically, we investigated if Kp(uu) could reconcile differences in CYP enzyme inhibition values (K-i or IC50). Firstly, our methodology for determination of Kp(uu) was optimized for human hepatocytes, using four well-studied reference compounds. Secondly, the methodology was applied to a series of structurally related CYP2C9 inhibitors from a Roche discovery project. Lastly, the Kp(uu) values of three commonly used CYP3A4 inhibitorsketoconazole, itraconazole, and posaconazolewere determined and compared to compound-specific hepatic enrichment factors obtained from physiologically based modeling of clinical DDI studies with these three compounds. Kp(uu) obtained in suspended human hepatocytes gave good predictions of system-dependent differences in vitro. The Kp(uu) was also in fair agreement with the compound-specific hepatic enrichment factors in DDI models and can therefore be used to improve estimations of enrichment factors in physiologically based pharmacokinetic modeling.

Place, publisher, year, edition, pages
SPRINGER , 2019. Vol. 21, no 5, article id 77
Keywords [en]
drug-drug interaction, intracellular bioavailability, physiologically based pharmacokinetic modeling, scaling factor, unbound drug concentrations
National Category
Pharmacology and Toxicology Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-390072DOI: 10.1208/s12248-019-0344-8ISI: 000472114600002PubMedID: 31214810OAI: oai:DiVA.org:uu-390072DiVA, id: diva2:1340964
Funder
EU, FP7, Seventh Framework Programme, 60751Swedish Research Council, 2822Swedish Research Council, 2017-01951Available from: 2019-08-07 Created: 2019-08-07 Last updated: 2019-08-07Bibliographically approved

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