title: Investigation of hepatobiliary disposition of doxorubicin following intrahepatic delivery of different dosage forms.
abstract: 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.
authors.affiliation: Department of Pharmacy, Uppsala University , Box 580, 751 23 Uppsala, Sweden.
authors.forename: Elsa
authors.initials: E
authors.lastname: Lilienberg
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ebeling Barbier
authors.forename: Rickard
authors.initials: R
authors.lastname: Nyman
authors.forename: Mikael
authors.initials: M
authors.lastname: Hedeland
authors.forename: Ulf
authors.initials: U
authors.lastname: Bondesson
authors.forename: Niklas
authors.initials: N
authors.lastname: Axén
authors.forename: Hans
authors.initials: H
authors.lastname: Lennernäs
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000493:pharmacokinetics*; D001652:Bile Ducts / Q000187:drug effects* / Q000378:metabolism / Q000601:surgery; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D004998:Ethiodized Oil / Q000737:chemistry; D006499:Hepatic Artery / Q000187:drug effects* / Q000378:metabolism / Q000601:surgery; D007261:Infusions, Intra-Arterial; D008297:Male; D013552:Swine; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: D000903:Antibiotics, Antineoplastic; D004998:Ethiodized Oil; D004317:Doxorubicin; C010013:adriamycinol