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Impact of intracellular bioavailability on metabolic drug-drug interactions
Uppsala University.
Roche Pharmaceutical Research and Early Development, Basel.
Roche Pharmaceutical Research and Early Development, Basel.
Roche Pharmaceutical Research and Early Development, Basel.
Visa övriga samt affilieringar
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Farmaceutiska vetenskaper
Identifikatorer
URN: urn:nbn:se:uu:diva-369686OAI: oai:DiVA.org:uu-369686DiVA, id: diva2:1271121
Tillgänglig från: 2018-12-16 Skapad: 2018-12-16 Senast uppdaterad: 2018-12-18
Ingår i avhandling
1. Characterization of parameters influencing intracellular bioavailability and prediction of intracellular drug exposure
Öppna denna publikation i ny flik eller fönster >>Characterization of parameters influencing intracellular bioavailability and prediction of intracellular drug exposure
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

This thesis work investigates factors influencing intracellular drug disposition. An experimental method for measurement of intracellular bioavailability (Fic), was used throughout. Fic is defined as the ratio between the unbound drug concentration inside the cell and the compound concentration in the cell exterior.

First, the impact of transporter proteins—such as the uptake transporter OATP-1B1 and the efflux transporter P-gp—on Fic was assessed in isolation in singly transfected, well-characterized cell models. The net impact of ADME proteins on Fic, including drug transporter proteins and metabolic enzymes, was assessed in primary human hepatocytes. The results indicated that the Fic measurement accurately reflected system-dependent functionality of these proteins.

Second, the impact of cellular lipids on Fic was studied, in particular phospholipids (a major constituent of cellular membranes) and neutral lipids (in the form of neutral lipid droplets in adipocytes). Drug partitioning to phospholipids was found to be the major determinant of intracellular fraction of unbound drug (fu,cell), while neutral lipid droplets and cellular proteins played a relatively smaller role. Therefore, the importance of phospholipids, and their major four subspecies—phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI)—was investigated in a cell-free approach with purified phospholipids.

Finally, Fic was applied in two ways to drug discovery settings. First, Fic successfully harmonized system-dependent CYP450 enzyme inhibition values (IC50) obtained in human hepatocytes and human liver microsomes. Fic measured in suspended human hepatocytes also reflected hepatic enrichment factors of CYP450 inhibitors used in physiologically-based pharmacokinetic modelling. Second, Fic was used as a complementary tool to study the effect of cell-penetrating peptides on intracellular disposition of targeted antisense oligonucleotide conjugates.

Overall, the thesis contributes to the mechanistic understanding of Fic and demonstrates its use for drug compound profiling at an early stage in drug discovery settings.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2019. s. 59
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 266
Nyckelord
intracellular drug bioavailability, unbound drug concentration, drug disposition, ADME, drug transport, drug metabolism membrane partitioning, phospholipid, drug-drug interaction, antisense oligonucleotide, cell-penetrating peptide
Nationell ämneskategori
Farmaceutiska vetenskaper
Forskningsämne
Farmaceutisk vetenskap
Identifikatorer
urn:nbn:se:uu:diva-369705 (URN)978-91-513-0542-4 (ISBN)
Disputation
2019-02-15, Room B41, BMC, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-01-23 Skapad: 2018-12-18 Senast uppdaterad: 2019-02-18

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