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Proteomics-informed prediction of rosuvastatin clearance in donors with and without obesity
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. (Läkemedelsformulering)ORCID-id: 0000-0002-2810-7518
DMPK, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. (Läkemedelsformulering)
Department of Pharmacy, University of Oslo, Oslo, Norway.
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nyckelord [en]
Proteomics, Plasma drug distribution, Pharmacokinetics, Uptake clearance, Prediction model
Nationell ämneskategori
Farmaceutiska vetenskaper
Forskningsämne
Farmaceutisk vetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-389740OAI: oai:DiVA.org:uu-389740DiVA, id: diva2:1338505
Tillgänglig från: 2019-07-23 Skapad: 2019-07-23 Senast uppdaterad: 2019-07-26
Ingår i avhandling
1. Proteomics-informed analysis of drug disposition in the human liver and small intestine
Öppna denna publikation i ny flik eller fönster >>Proteomics-informed analysis of drug disposition in the human liver and small intestine
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Orally administered drugs are absorbed in the intestine and generally metabolized in the liver. Therefore, understanding factors determining drug distribution and elimination in these tissues is important. This thesis aimed at using mass spectrometry (MS)-based proteomics and functional studies to better understand in vitro model systems used for drug clearance predictions. Further, it aimed at understanding the changes in drug disposition caused by obesity and gastric bypass surgery (GBP).

The study was initiated by investigating factors influencing MS-based protein quantification by comparing results from different proteomics methods, and by studying protein distribution during subcellular fractionation. The largest variability in protein quantification was ascribed to insufficient enrichment from subcellular fractionation, most likely due to collection of the majority of the proteins in the initial fraction of the fractionation protocols.

Proteomics and metabolic activity analyses were then used to investigate differences in intrinsic clearance from two commonly used in vitro systems, human liver microsomes and hepatocytes. For some compounds, the faster microsomal metabolism could be explained by a higher available unbound drug concentration and CYP content in the microsomes as compared to in the hepatocytes.

Next, inter-individual protein expression variability in human liver and jejunum was explored. This showed that proteins covered a wide inter-individual variability spectrum, in which proteins with low variabilities were associated with essential cellular functions, while many proteins with high variabilities were disease-related.

Further, the effects of obesity, GBP, and weight loss on the proteomes of human liver and jejunum were analyzed. After GBP and subsequent weight loss, patients showed lower levels of jejunal proteins involved in inflammatory response and drug metabolism.

Finally, proteomics data from patients with and without obesity was combined with parameters from in vitro transport kinetics, and a mechanistic model to predict drug disposition was developed. The model successfully predicted rosuvastatin plasma concentrations in the patients.

In conclusion, this thesis has provided insights into factors influencing protein quantification and function in vitro. Furthermore, this thesis demonstrates how proteomics contributes to improved understanding of inter-individual and physiological differences, and how it can be used for in vitro-in vivo scaling of drug clearance.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2019. s. 79
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 273
Nyckelord
proteomics, protein concentration, drug disposition, drug transport, drug metabolism, human small intestine, human liver, human hepatocytes, human liver microsomes, inter-individual variability, drug clearance, obesity, prediction model
Nationell ämneskategori
Farmaceutiska vetenskaper
Forskningsämne
Farmaceutisk vetenskap
Identifikatorer
urn:nbn:se:uu:diva-389741 (URN)978-91-513-0694-0 (ISBN)
Disputation
2019-09-13, B42, Biomedical center, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-08-22 Skapad: 2019-07-26 Senast uppdaterad: 2019-08-22

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Wegler, ChristineArtursson, Per

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