title: Doxorubicin: Comparison between 3-h continuous and bolus intravenous administration paradigms on cardio-renal axis, mitochondrial sphingolipids and pathology.
abstract: Doxorubicin (DOX) is a potent and effective broad-spectrum anthracycline antitumor agent, but its clinical usefulness is restricted by cardiotoxicity. This study compared pharmacokinetic, functional, structural and biochemical effects of single dose DOX bolus or 3-h continuous iv infusion (3-h iv) in the Han–Wistar rat to characterize possible treatment-related differences in drug safety over a 72 h observation period. Both DOX dosing paradigms significantly altered blood pressure, core body temperature and QA interval (indirect measure of cardiac contractility); however, there was no recovery observed in the bolus iv treatment group. Following the 3-h iv treatment, blood pressures and QA interval normalized by 36 h then rose above baseline levels over 72 h. Both treatments induced biphasic changes in heart rate with initial increases followed by sustained decreases. Cardiac injury biomarkers in plasma were elevated only in the bolus iv treatment group. Tissue cardiac injury biomarkers, cardiac mitochondrial complexes I, III and V and cardiac mitochondrial sphingolipids were decreased only in the bolus iv treatment group. Results indicate that each DOX dosing paradigm deregulates sinus rhythm.However, slowing the rate of infusion allows for functional compensation of blood pressure and may decrease the likelihood of cardiac myocyte necrosis via a mechanism associated with reduced mitochondrial damage.
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Waltham, MA 02451, USA. Electronic address: harriet_kamendi@kandih.com.
authors.forename: Harriet
authors.initials: H
authors.lastname: Kamendi
authors.affiliation: Oncology Innovative Medicines and Early Development, AstraZeneca, Waltham, MA 02451, USA. Electronic address: yingzhou526@gmail.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Waltham, MA 02451, USA. Electronic address: Meredith.crosby@astrazeneca.com.
authors.forename: Meredith
authors.initials: M
authors.lastname: Crosby
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Waltham, MA 02451, USA. Electronic address: Nkeirstead@alnylam.com.
authors.forename: Natalie
authors.initials: N
authors.lastname: Keirstead
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Waltham, MA 02451, USA. Electronic address: Debra.snow@astrazeneca.com.
authors.forename: Debra
authors.initials: D
authors.lastname: Snow
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Waltham, MA 02451, USA. Electronic address: patricia.bentley@abbvie.com.
authors.forename: Patricia
authors.initials: P
authors.lastname: Bentley
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Waltham, MA 02451, USA. Electronic address: patelnilaben@yahoo.com.
authors.forename: Nilaben
authors.initials: N
authors.lastname: Patel
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Waltham, MA 02451, USA. Electronic address: Herbert.barthlow@astrazeneca.com.
authors.forename: Herbert
authors.initials: H
authors.lastname: Barthlow
authors.affiliation: Discovery Sciences, Innovative Medicines, AstraZeneca, Waltham, MA 02451, USA. Electronic address: Wenli.luo@astrazeneca.com.
authors.forename: Wenli
authors.initials: W
authors.lastname: Luo
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Waltham, MA 02451, USA. Electronic address: Yvonne.P.Dragan@takeda.com.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Dragan
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Waltham, MA 02451, USA. Electronic address: russell.bialecki@astrazeneca.com.
authors.forename: Russell
authors.initials: R
authors.lastname: Bialecki
mesh_terms: D061605:Administration, Intravenous / Q000379:methods; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D013107:Sphingolipids / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D013107:Sphingolipids; D004317:Doxorubicin
keywords: Cardiotoxicity; Doxorubicin; Intravenous infusion; Mitochondrial toxicity; Sphingolipids