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The Effects of Lipiodol and Cyclosporin A on the Hepatobiliary Disposition of Doxorubicin in Pigs
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
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2014 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, no 4, 1301-1313 p.Article in journal (Refereed) Published
Abstract [en]

Doxorubicin (DOX) emulsified in Lipiodol (LIP) is used as local palliative treatment for unresectable intermediate stage hepatocellular carcinoma. The objective of this study was to examine the poorly understood effects of the main excipient in the drug delivery system, LIP, alone or together with cyclosporin A (CsA), on the in vivo liver disposition of DOX. The advanced, multi-sampling-site, acute pig model was used; samples were collected from three blood vessels (v. portae, v. hepatica and v. femoralis), bile and urine. The four treatment groups (TI-TIV) all received two intravenous 5 min infusions of DOX into an ear vein: at 0 and 200 min. Before the second dose, the pigs received a portal vein infusion of saline (TI), LIP (TII), CsA (TIII) or LIP and CsA (TIV). Concentrations of DOX and its active metabolite doxorubicinol (DOXol) were analyzed using UPLC-MS/MS. A multi-compartment model was developed to describe the distribution of DOX and DOXol in plasma, bile and urine. LIP did not affect the pharmacokinetics of DOX or DOXol. CsA (TIII and TIV) had no effect on the plasma pharmacokinetics of DOX, but a 2-fold increase in exposure to DOXol and a significant decrease in hepatobiliary clearance of DOX and DOXol was observed. Model simulations supported that CsA inhibits 99% of canalicular biliary secretion of both DOX and DOXol, but does not affect the metabolism of DOX to DOXol. In conclusion, LIP did not interact with transporters, enzymes and/or biological membranes important for the hepatobiliary disposition of DOX.

Place, publisher, year, edition, pages
2014. Vol. 11, no 4, 1301-1313 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-222282DOI: 10.1021/mp4007612ISI: 000334092700022PubMedID: 24558959OAI: oai:DiVA.org:uu-222282DiVA: diva2:711164
Available from: 2014-04-09 Created: 2014-04-09 Last updated: 2017-12-05Bibliographically approved
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
2. Biopharmaceutical investigations of doxorubicin formulations used in liver cancer treatment: Studies in healthy pigs and liver cancer patients, combined with pharmacokinetic and biopharmaceutical modelling
Open this publication in new window or tab >>Biopharmaceutical investigations of doxorubicin formulations used in liver cancer treatment: Studies in healthy pigs and liver cancer patients, combined with pharmacokinetic and biopharmaceutical modelling
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There are currently two types of drug formulation in clinical use in the locoregional treatment of intermediate hepatocellular carcinoma (HCC). In the emulsion LIPDOX, the cytostatic agent doxorubicin (DOX) is dissolved in the aqueous phase, which is emulsified with the oily contrast agent Lipiodol® (LIP). In the microparticular system DEBDOX, DOX is loaded into the drug-eluting entity DC Bead™.

The overall aim of the thesis was to improve pharmaceutical understanding of the LIPDOX and DEBDOX formulations, in order to facilitate the future development of novel drug delivery systems. In vivo release of DOX from the formulations and the disposition of DOX and its active metabolite doxorubicinol (DOXol) were assessed in an advanced multisampling-site acute healthy pig model and in patients with HCC. The release of DOX and disposition of DOX and DOXol where further analysed using physiologically based pharmacokinetic (PBPK) and biopharmaceutical (PBBP) modelling. The combination of in vivo investigations and in silico modelling could provide unique insight into the mechanisms behind drug release and disposition.

The in vivo release of DOX from LIPDOX is not extended and controlled, as it is from DEBDOX. With both formulations, DOX is released as a burst during the early phase of administration. The in vivo release of DOX from LIPDOX was faster than from DEBDOX in both pigs and patients. The release from DEBDOX was slow and possibly incomplete. The in vivo release of DOX from LIPDOX and DEBDOX could be described by using the PBBP model in combination with in vitro release profiles.

The disposition of DOX and DOXol was modelled using a semi-PBPK model containing intracellular binding sites. The contrast agent Lipiodol® did not affect the hepatobiliary disposition of DOX in the pig model. The control substance used in this study, cyclosporine A, inhibited the biliary excretion of DOX and DOXol but did not alter metabolism in healthy pigs. The disposition of DOX is similar in healthy pigs and humans, which was shown by the ease of translation of the semi-PBPK pig model to the human PBBP model.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 70 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 240
Keyword
drug delivery system, in vivo release, PBPK modelling, hepatocellular carcinoma, doxorubicin, transarterial chemoembolization, drug disposition
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics; Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-330953 (URN)978-91-513-0124-2 (ISBN)
Public defence
2017-12-08, B41, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2017-11-16 Created: 2017-10-21 Last updated: 2017-11-16

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Dubbelboer, Ilse RLilienberg, ElsaHedeland, MikaelBondesson, UlfSjögren, ErikLennernäs, Hans

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