title: Mechanism of the cardioprotective effects of docetaxel pre-administration against adriamycin-induced cardiotoxicity.
abstract: We revealed that pre-treatment with docetaxel (DOC) 12 h before adriamycin (ADR) administration significantly reduced ADR-induced toxic death compared with the simultaneous dosing schedule that was commonly used in previous studies. We considered that pre-treatment with DOC relieves ADR-induced cardiotoxicity. In this study, we investigated the influence of DOC on the pharmacokinetics and pharmacodynamics of ADR in order to clarify the mechanism by which DOC pre-treatment relieves ADR-induced cardiotoxicity. When ADR and/or DOC was intravenously administered, the DOC pre-treatment (DOC-ADR) group showed significantly less toxic death than the ADR-alone group. We examined hepatopathy, nephropathy, leukopenia, and cardiotoxicity, all of which can cause toxic death. Of these toxicities, ADR-induced cardiotoxicity was significantly relieved in the DOC-ADR group. To elucidate the mechanism by which DOC pre-treatment relieved ADR-induced cardiotoxicity, lipid peroxidation as a proxy for the free radical level and the pharmacokinetics of ADR were measured. There was no difference in the pharmacokinetics of ADR between the ADR and DOC-ADR groups. On the other hand, the DOC-ADR group showed significantly inhibited lipid peroxidation in the heart compared with the ADR group. It was considered that DOC pre-administration inhibited ADR-induced free radicals and decreased cardiotoxicity.
authors.affiliation: Department of Hospital Pharmacy, Nagasaki University Hospital, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Tomonari
authors.forename: Hideto
authors.initials: H
authors.lastname: To
authors.forename: Motohiro
authors.initials: M
authors.lastname: Nishida
authors.forename: Takashi
authors.initials: T
authors.lastname: Mishima
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sasaki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kurose
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D054715:Cardiotoxins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004562:Electrocardiography / Q000187:drug effects; D005609:Free Radicals / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006331:Heart Diseases / Q000139:chemically induced* / Q000401:mortality; D007958:Leukocyte Count; D015227:Lipid Peroxidation / Q000187:drug effects; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D043823:Taxoids / Q000008:administration & dosage*; D013997:Time Factors
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D002316:Cardiotonic Agents; D054715:Cardiotoxins; D005609:Free Radicals; D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin