Mechanism of the cardioprotective effects of docetaxel pre-administration against adriamycin-induced cardiotoxicity

J Pharmacol Sci. 2011;115(3):336-45. doi: 10.1254/jphs.10279fp. Epub 2011 Feb 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / administration & dosage
  • Antibiotics, Antineoplastic / pharmacokinetics
  • Antibiotics, Antineoplastic / pharmacology
  • Antibiotics, Antineoplastic / toxicity*
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols
  • Cardiotonic Agents / administration & dosage*
  • Cardiotoxins / administration & dosage
  • Cardiotoxins / pharmacokinetics
  • Cardiotoxins / pharmacology
  • Cardiotoxins / toxicity*
  • Docetaxel
  • Doxorubicin / administration & dosage
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / toxicity*
  • Electrocardiography / drug effects
  • Free Radicals / metabolism
  • Heart / drug effects*
  • Heart Diseases / chemically induced*
  • Heart Diseases / mortality
  • Leukocyte Count
  • Lipid Peroxidation / drug effects
  • Liver Function Tests
  • Male
  • Mice
  • Mice, Inbred ICR
  • Taxoids / administration & dosage*
  • Time Factors

Substances

  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • Cardiotonic Agents
  • Cardiotoxins
  • Free Radicals
  • Taxoids
  • Docetaxel
  • Doxorubicin