The Effects of Lipiodol and Cyclosporin A on the Hepatobiliary Disposition of Doxorubicin in Pigs

Abstract

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 and its active metabolite doxorubicinol (DOXol). 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 DOXol were analyzed using UPLC-MS/MS. The developed multicompartment model described 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 were 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 directly interact with transporters, enzymes and/or biological membranes important for the hepatobiliary disposition of DOX.

Lipiodol does not affect the tissue distribution of intravenous doxorubicin infusion in pigs

“…This preclinical study was designed to investigate how lipiodol, administered separately from DOX, affects the tissue concentration and distribution ( K p ) of DOX and DOXol. The first part of the study, regarding multiple site plasma PK and biliary and urinary excretion, has been published previously . The materials and methods used in the in vivo experiment in this second part of the study have been described in detail in the previous article .…”

“…In healthy pig liver, the intracellular concentrations of DOX tended to be higher (78%) after administration of a DOX‐in‐lipiodol emulsion than after administration of DOX‐loaded microparticles . In a subsequent pharmacokinetic (PK) pig study, it was concluded that lipiodol alters neither the plasma concentrations nor the biliary and urinary excretion of DOX and DOXol . That pig study also concluded that ciclosporin (CsA) alters the disposition of DOX and DOXol, probably by inhibition of canalicular biliary secretion .…”

“…In a subsequent pharmacokinetic (PK) pig study, it was concluded that lipiodol alters neither the plasma concentrations nor the biliary and urinary excretion of DOX and DOXol . That pig study also concluded that ciclosporin (CsA) alters the disposition of DOX and DOXol, probably by inhibition of canalicular biliary secretion . Those conclusions were based on PK parameters obtained from collected blood (three different sites), bile and urine samples from an advanced multiple sampling site pig model.…”

“…CsA was used as a positive control as it is known to inhibit the carrier‐mediated transporters that are important for DOX efflux, namely P‐glycoprotein (Pgp), breast cancer resistance protein (BCRP), multidrug resistance‐associated protein 2 (MRP2) and the organic anion‐transporting polypeptide (OATP) family . This study is part of the liver cancer treatment‐optimisation project at Uppsala University …”

Improved stability of lipiodol–drug emulsion for transarterial chemoembolisation of hepatocellular carcinoma results in improved pharmacokinetic profile: Proof of concept using idarubicin

“…This point is of major interest as very recently demonstrated in a pig model, which showed that the in vivo distribution of the drug was affected more by the formulation-related properties of the anticancer drug-lipiodol emulsion than by any direct interactions between lipiodol and membrane barriers and/or transport proteins [30].…”