title: Comparison of drug release and pharmacokinetics after transarterial chemoembolization using diverse lipiodol emulsions and drug-eluting beads.
abstract: In many studies for chemoembolization of hepatocellular carcinoma, the Lipiodol emulsion preparation protocols, especially the mixing steps, were unclear or even unrevealed at all. However, doxorubicin (DOX) release may depend on the composition and volume ratio (Lipiodol to DOX solution) of a Lipiodol emulsion. Therefore, we conducted a preclinical study to compare in-vitro drug release and in-vivo pharmacokinetics of DOX from diverse Lipiodol emulsions and drug-eluting beads (DEBs) and to compare the tumor response in a rabbit VX2 carcinoma model. DOX release profiles of four types of Lipiodol emulsions with different media (normal saline or Pamiray as an iodinated contrast medium), volume ratio (Lipiodol to DOX solution), and DEBs were investigated in-vitro. For the in-vivo study, 15 rabbits bearing VX2 carcinoma in the liver were treated with 4∶1 volume ratio Lipiodol emulsion (group A), 1∶1 volume ratio Lipiodol emulsion (group B), and DEBs (group C) chemoembolization. Blood and tissue sampling was conducted to evaluate DOX concentration in plasma and tissues, histological changes, and liver toxicity. The most stable emulsion was formed with Pamiray (including DOX) at a 4∶1 volume ratio. The AUC value of group A was significantly lower than that of group B (p = 0.003) but comparable to that of group C (p = 0.071). The Cmax value of group A was significantly different compared with those of group B (p = 0.004) and C (p = 0.015). The tissue drug concentration in group A was comparable to that in group C (p = 0.251). No viable tumor was detected in rabbits of group A and B. In group C, viable tumor less than 10% was seen in two of the five rabbits. There were no significant differences in liver enzyme levels after the procedure. In conclusion, DOX release and pharmacokinetics of presented emulsion systems depend substantially on their composition. Therefore, Lipiodol emulsion type should be considered when interpreting data and designing new studies dealing with chemoembolization.
authors.affiliation: Department of Radiology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Kangwon National University, Chuncheon, Korea.
authors.forename: Hyun-Jong
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: Ju-Hwan
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Radiology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Song Yi
authors.initials: SY
authors.lastname: Baek
authors.affiliation: Department of Radiology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Jin Wook
authors.initials: JW
authors.lastname: Chung
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: Dae-Duk
authors.initials: DD
authors.lastname: Kim
authors.affiliation: Department of Radiology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Hyo-Cheol
authors.initials: HC
authors.lastname: Kim
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D016461:Chemoembolization, Therapeutic / Q000379:methods*; D004317:Doxorubicin / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004337:Drug Carriers / Q000493:pharmacokinetics / Q000627:therapeutic use; D065546:Drug Liberation; D004655:Emulsions / Q000627:therapeutic use; D004998:Ethiodized Oil / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000188:drug therapy*; D008863:Microspheres; D011817:Rabbits
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D004655:Emulsions; D004998:Ethiodized Oil; D004317:Doxorubicin