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Comparison of drug release, pharmacokinetics and pharmacodynamics after lipiodol-based emulsion or drug-eluting bead delivery to patients with hepatocellular carcinoma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Institutionen för Radiologi, Karolinska Universitetssjukhuset i Huddinge; Institutionen för klinisk vetenskap, intervention och teknologi, Karolinska institutet, Stockholm .
Institutionen för Radiologi, Karolinska Universitetssjukhuset i Huddinge; Institutionen för klinisk vetenskap, intervention och teknologi, Karolinska institutet, Stockholm .
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(English)Manuscript (preprint) (Other academic)
Keyword [en]
Doxorubicin, doxorubicinol, drug eluting beads, focal delivery, focal therapy, hepatocellular carcinoma, liver cancer, lipiodol, transarterial chemoembolization, transarterial infusion chemotherapy
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-267395OAI: oai:DiVA.org:uu-267395DiVA: diva2:872996
Funder
Swedish Research Council, 521-2011-373
Available from: 2015-11-21 Created: 2015-11-21 Last updated: 2016-01-13
In thesis
1. Biopharmaceutical Evaluation of Intra-arterial Drug-Delivery Systems for Liver Cancer: Investigations in healthy pigs and liver cancer patients
Open this publication in new window or tab >>Biopharmaceutical Evaluation of Intra-arterial Drug-Delivery Systems for Liver Cancer: Investigations in healthy pigs and liver cancer patients
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There are currently two types of intra-arterial drug-delivery system (DDS) in clinical use in the palliative treatment of primary liver cancer. The chemotherapeutic drug doxorubicin (DOX) can be formulated into a drug-in-lipiodol emulsion (LIPDOX) or a microparticulate drug-eluting bead system (DEBDOX). To facilitate development of future DDSs, we need to understand the release and local distribution of drug from these DDSs into the complex, in vivo, pathological environment.

The overall aim of this project was to assess and improve understanding of the in vivo release of DOX from LIPDOX and DEBDOX and its local disposition in the liver. These processes were investigated in detail in a multisampling-site, healthy pig model and in human patients with liver cancer. The mechanisms involved in DOX disposition were studied by examining potential interactions between DOX and lipiodol and/or cyclosporine A (CsA) in pigs.  

In this project, the main elimination pathway for DOX and its primary metabolite doxorubicinol (DOXol) was via bile; their extensive canalicular carrier-mediated transport (e.g. ATP-binding cassette transporters ABCB1, ABCC1, ABCC2 and ABCG2) was inhibited by CsA. CsA had no effect on the carbonyl and aldo-keto reductases responsible for the metabolism of DOX into DOXol. LIPDOX released DOX more rapidly and to a greater extent into the circulation than DEBDOX, which had only released 15% of the dose in patients after 24 hrs. The systemic exposure to DOX was lower for DEBDOX than for LIPDOX. Greater fractions of DOXol were formed in blood and bile with LIPDOX than with DEBDOX. This may have been because DOX was more widely distributed into regions with increased metabolic capacity or because of increased intracellular uptake when DOX was delivered in LIPDOX. The excipient lipiodol in the LIPDOX formulation did not interact with transporters, enzymes or membranes that would explain the increased cellular uptake of DOX.

In conclusion, the release of DOX from DEBDOX is more controlled in vivo than that from LIPDOX, indicating that DEBDOX is a more robust pharmaceutical product. The formulations for future optimized DDSs should therefore be more similar to DEBDOX than to LIPDOX. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 207
Keyword
in vivo release, drug delivery systems, local delivery, drug disposition, doxorubicin, hepatocellular carcinoma, transarterial chemoembolization, transarterial chemotherapy infusion
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-267396 (URN)978-91-554-9422-3 (ISBN)
Public defence
2016-01-22, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Funder
Swedish Research Council
Available from: 2015-12-22 Created: 2015-11-21 Last updated: 2016-01-13

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