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Improved predictions of time-dependent drug-drug interactions by determination of cytosolic drug concentrations
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (Department of Pharmacy and Uppsala Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala University, BMC, Box 580, SE-75123, Uppsala, Sweden.)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (Department of Pharmacy and Uppsala Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala University, BMC, Box 580, SE-75123, Uppsala, Sweden.)ORCID iD: 0000-0001-8650-1225
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (Department of Pharmacy and Uppsala Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala University, BMC, Box 580, SE-75123, Uppsala, Sweden.)ORCID iD: 0000-0001-6870-0677
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab. (Department of Pharmacy and Uppsala Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala University, BMC, Box 580, SE-75123, Uppsala, Sweden.)
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 5850Article in journal (Refereed) Published
Abstract [en]

The clinical impact of drug-drug interactions based on time-dependent inhibition of cytochrome P450 (CYP) 3A4 has often been overpredicted, likely due to use of improper inhibitor concentration estimates at the enzyme. Here, we investigated if use of cytosolic unbound inhibitor concentrations could improve predictions of time-dependent drug-drug interactions. First, we assessed the inhibitory effects of ten time-dependent CYP3A inhibitors on midazolam 1′-hydroxylation in human liver microsomes. Then, using a novel method, we determined the cytosolic bioavailability of the inhibitors in human hepatocytes, and used the obtained values to calculate their concentrations at the active site of the enzyme, i.e. the cytosolic unbound concentrations. Finally, we combined the data in mechanistic static predictions, by considering different combinations of inhibitor concentrations in intestine and liver, including hepatic concentrations corrected for cytosolic bioavailability. The results were then compared to clinical data. Compared to no correction, correction for cytosolic bioavailability resulted in higher accuracy and precision, generally in line with those obtained by more demanding modelling. The best predictions were obtained when the inhibition of hepatic CYP3A was based on unbound maximal inhibitor concentrations corrected for cytosolic bioavailability. Our findings suggest that cytosolic unbound inhibitor concentrations improves predictions of time-dependent drug-drug interactions for CYP3A.

Place, publisher, year, edition, pages
2019. Vol. 9, article id 5850
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-382453DOI: 10.1038/s41598-019-42051-xISI: 000463984600008OAI: oai:DiVA.org:uu-382453DiVA, id: diva2:1307093
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Swedish Research Council, 01951Available from: 2019-04-25 Created: 2019-04-25 Last updated: 2019-05-03Bibliographically approved

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