title: Distinct biodistribution of doxorubicin and the altered dispositions mediated by different liposomal formulations.
abstract: The liposomal formulations of doxorubicin produced distinct efficacy and toxicity profiles compared to doxorubicin solution in cancer patients. This study aims to investigate the drug tissue distribution and the driving force for tissue distribution from doxorubicin solution and two liposomal delivery systems, Doxil and Myocet. These three formulations were intravenously administered to mice at a single dose of 5mg/kg. Eleven organs, plasma and blood were collected at different time points. Total doxorubicin concentrations in each specimen were measured with LC-MS/MS. Compared to doxorubicin solution, both Doxil and Myocet produced distinct doxorubicin tissue exposure in all 11 tissues. Interestingly, the tissue exposure by Myocet was drastically different from that of Doxil and showed a formulation-dependent pattern. Cmax of doxorubicin in heart tissue by Doxil and Myocet was approximately 60% and 50% respectively of that by doxorubicin solution. The predominant driving force for doxorubicin tissue distribution is liposomal-doxorubicin deposition for Doxil and free drug concentration for doxorubicin solution. For Myocet, the driving force for tissue distribution is predominately liposomal-doxorubicin deposition into tissues within the first 4h; as the non-PEGylated doxorubicin liposomal decomposes, the driving force for tissue distribution is gradually switched to the released free doxorubicin. Unique tissue distributions are correlated with their toxicity profiles.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI 48109, United States.
authors.forename: Ruijuan
authors.initials: R
authors.lastname: Luo
authors.affiliation: Translational Development and Clinical Pharmacology, Celgene Corporation, 86 Morris Avenue, Summit, NJ 07920, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI 48109, United States.
authors.forename: Miao
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI 48109, United States.
authors.forename: Huixia
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI 48109, United States.
authors.forename: Hebao
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI 48109, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Johnson
authors.affiliation: Translational Development and Clinical Pharmacology, Celgene Corporation, 86 Morris Avenue, Summit, NJ 07920, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Palmisano
authors.affiliation: Translational Development and Clinical Pharmacology, Celgene Corporation, 86 Morris Avenue, Summit, NJ 07920, United States.
authors.forename: Simon
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI 48109, United States. Electronic address: duxins@med.umich.edu.
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002853:Chromatography, Liquid / Q000379:methods; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D005260:Female; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism; D012996:Solutions / Q000737:chemistry; D053719:Tandem Mass Spectrometry / Q000379:methods; D014018:Tissue Distribution / Q000502:physiology*
chemical_list: D008081:Liposomes; D012996:Solutions; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Doxorubicin; Drug delivery; Liposome; Tissue distribution