Sökning: onr:"swepub:oai:DiVA.org:uu-382453" >
Improved prediction...
Improved predictions of time-dependent drug-drug interactions by determination of cytosolic drug concentrations
-
- Filppula, Anne M. (författare)
- Uppsala universitet,Institutionen för farmaci,Department of Pharmacy and Uppsala Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala University, BMC, Box 580, SE-75123, Uppsala, Sweden.
-
- Parvizi, Rezvan (författare)
- Uppsala universitet,Institutionen för farmaci,Department of Pharmacy and Uppsala Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala University, BMC, Box 580, SE-75123, Uppsala, Sweden.
-
- Mateus, André, 1986- (författare)
- Uppsala universitet,Institutionen för farmaci,Department of Pharmacy and Uppsala Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala University, BMC, Box 580, SE-75123, Uppsala, Sweden.
-
visa fler...
-
- Baranczewski, Pawel (författare)
- Uppsala universitet,Institutionen för farmaci,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.
-
- Artursson, Per (författare)
- Uppsala universitet,Institutionen för farmaci,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.
-
visa färre...
-
(creator_code:org_t)
- 2019-04-10
- 2019
- Engelska.
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
- Relaterad länk:
-
https://doi.org/10.1...
-
visa fler...
-
https://uu.diva-port... (primary) (Raw object)
-
https://doi.org/10.1...
-
https://urn.kb.se/re...
-
https://doi.org/10.1...
-
visa färre...
Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
Till lärosätets databas