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Biopharmaceutical Evaluation of Intra-arterial Drug-Delivery Systems for Liver Cancer: Investigations in healthy pigs and liver cancer patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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 [en]
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: urn:nbn:se:uu:diva-267396ISBN: 978-91-554-9422-3 (print)OAI: oai:DiVA.org:uu-267396DiVA: diva2:873356
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
List of papers
1. Investigation of Hepatobiliary Disposition of Doxorubicin Following Intrahepatic Delivery of Different Dosage Forms
Open this publication in new window or tab >>Investigation of Hepatobiliary Disposition of Doxorubicin Following Intrahepatic Delivery of Different Dosage Forms
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2014 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, no 1, 131-144 p.Article in journal (Refereed) Published
Abstract [en]

Unresectable, intermediate stage hepatocellular carcinoma (HCC) is often treated palliatively in humans by doxorubicin (DOX). The drug is administered either as a drug-emulsified-in-Lipiodol (DLIP) or as drug loaded into drug eluting beads (DEB), and both formulations are administered intrahepatically. However, several aspects of their in vivo performance in the liver are still not well-understood. In this study, DLIP and DEB were investigated regarding the local and systemic pharmacokinetics (PK) of DOX and its primary metabolite doxorubicinol (DOXol). An advanced PK-multisampling site acute in vivo pig model was used for simultaneous sampling in the portal, hepatic, and femoral veins and the bile duct. The study had a randomized, parallel design with four treatment groups (TI–TIV). TI (n = 4) was used as control and received an intravenous (i.v.) infusion of DOX as a solution. TII and TIII were given a local injection in the hepatic artery with DLIP (n = 4) or DEB (n = 4), respectively. TIV (n = 2) received local injections of DLIP in the hepatic artery and bile duct simultaneously. All samples were analyzed for concentrations of DOX and DOXol with UPLC-MS/MS. Compared to DLIP, the systemic exposure for DOX with DEB was reduced (p < 0.05), in agreement with a slower in vivo release. The approximated intracellular bioavailability of DOX during 6 h appeared to be lower for DEB than DLIP. Following i.v. infusion (55 min), DOX had a liver extraction of 41 (28–53)%, and the fraction of the dose eliminated in bile of DOX and DOXol was 20 (15–22)% and 4.2 (3.2–5.2)%, respectively. The AUCbile/AUCVP for DOX and DOXol was 640 (580–660) and 5000 (3900–5400), respectively. In conclusion, DLIP might initially deliver a higher hepatocellular concentration of DOX than DEB as a consequence of its higher in vivo release rate. Thus, DLIP delivery results in higher intracellular peak concentrations that might correlate with better anticancer effects, but also higher systemic drug exposure and safety issues.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-210381 (URN)10.1021/mp4002574 (DOI)000329529700012 ()24171458 (PubMedID)
Available from: 2013-11-06 Created: 2013-11-06 Last updated: 2017-12-06Bibliographically approved
2. The Effects of Lipiodol and Cyclosporin A on the Hepatobiliary Disposition of Doxorubicin in Pigs
Open this publication in new window or tab >>The Effects of Lipiodol and Cyclosporin A on the Hepatobiliary Disposition of Doxorubicin in Pigs
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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.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-222282 (URN)10.1021/mp4007612 (DOI)000334092700022 ()24558959 (PubMedID)
Available from: 2014-04-09 Created: 2014-04-09 Last updated: 2017-12-05Bibliographically approved
3. Lipiodol does not affect the tissue distribution of intravenous doxorubicin infusion in pigs
Open this publication in new window or tab >>Lipiodol does not affect the tissue distribution of intravenous doxorubicin infusion in pigs
(English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392Article in journal (Other academic) Submitted
Abstract
Place, publisher, year, edition, pages
Uppsala:
Keyword
doxorubicin, doxorubicinol, lipiodol, tissue distribution, Kp, cyclosporine A
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-267119 (URN)
Available from: 2015-11-21 Created: 2015-11-18 Last updated: 2017-12-01
4. Comparison of drug release, pharmacokinetics and pharmacodynamics after lipiodol-based emulsion or drug-eluting bead delivery to patients with hepatocellular carcinoma
Open this publication in new window or tab >>Comparison of drug release, pharmacokinetics and pharmacodynamics after lipiodol-based emulsion or drug-eluting bead delivery to patients with hepatocellular carcinoma
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(English)Manuscript (preprint) (Other academic)
Keyword
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:nbn:se:uu:diva-267395 (URN)
Funder
Swedish Research Council, 521-2011-373
Available from: 2015-11-21 Created: 2015-11-21 Last updated: 2016-01-13

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