Sökning: id:"swepub:oai:DiVA.org:uu-389737" >
Influence of Proteo...
Influence of Proteome Profiles and Intracellular Drug Exposure on Differences in CYP Activity in Donor-Matched Human Liver Microsomes and Hepatocytes
-
- Wegler, Christine (författare)
- Uppsala universitet,Institutionen för farmaci,DMPK, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, 431 50 Gothenburg, Sweden,Läkemedelsformulering
-
- Matsson, Pär, 1978- (författare)
- Uppsala universitet,Institutionen för farmaci,Läkemedelsformulering
-
- Krogstad, Veronica (författare)
- Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo
-
visa fler...
-
- Urdzik, Jozef (författare)
- Uppsala universitet,Gastrointestinalkirurgi
-
- Christensen, Hege (författare)
- Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo
-
- Andersson, Tommy B. (författare)
- DMPK, Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg
-
- Artursson, Per (författare)
- Uppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab,Läkemedelsformulering
-
visa färre...
-
(creator_code:org_t)
- 2021-03-19
- 2021
- Engelska.
-
Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 18:4, s. 1792-1805
- Relaterad länk:
-
https://doi.org/10.1...
-
visa fler...
-
https://uu.diva-port... (primary) (Raw object)
-
https://pubs.acs.org...
-
https://urn.kb.se/re...
-
https://doi.org/10.1...
-
visa färre...
Abstract
Ämnesord
Stäng
- Human liver microsomes (HLM) and human hepatocytes (HH) are important in vitro systems for studies of intrinsic drug clearance (CLint) in the liver. However, the CLint values are often in disagreement for these two systems. Here, we investigated these differences in a side-by-side comparison of drug metabolism in HLM and HH prepared from 15 matched donors. Protein expression and intracellular unbound drug concentration (Kpuu) effects on the CLint were investigated for five prototypical probe substrates (bupropion–CYP2B6, diclofenac–CYP2C9, omeprazole–CYP2C19, bufuralol–CYP2D6, and midazolam–CYP3A4). The samples were donor-matched to compensate for inter-individual variability but still showed systematic differences in CLint. Global proteomics analysis outlined differences in HLM from HH and homogenates of human liver (HL), indicating variable enrichment of ER-localized cytochrome P450 (CYP) enzymes in the HLM preparation. This suggests that the HLM may not equally and accurately capture metabolic capacity for all CYPs. Scaling CLint with CYP amounts and Kpuu could only partly explain the discordance in absolute values of CLint for the five substrates. Nevertheless, scaling with CYP amounts improved the agreement in rank order for the majority of the substrates. Other factors, such as contribution of additional enzymes and variability in the proportions of active and inactive CYP enzymes in HLM and HH, may have to be considered to avoid the use of empirical scaling factors for prediction of drug metabolism.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- Human liver microsomes
- Human hepatocytes
- Proteomics
- Kpuu
- drug metabolic clearance
- Pharmaceutical Science
- Farmaceutisk vetenskap
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
Till lärosätets databas