The relative toxicity of intravenous and intraperitoneal doses of epirubicin.
The toxicity of single doses of the anthracycline epirubicin was compared in the rat after either the intravenous (i.v.; 2-6 mg/kg) or intraperitoneal (i.p.; 4-8 mg/kg) administration of the drug. These doses produced comparable acute toxicity that was characterised by a dose-dependent, transient reduction in body weight (less than 15%) in the first 2 weeks after drug administration. Sequential measurements of cardiac output in animals that received i.v. doses of epirubicin showed that the time-related changes in cardiac function were biphasic. There was an initial decline in cardiac output in the first 12 weeks, which was followed by a phase of persistent depression in cardiac output between 12 weeks and 20 weeks. The time-related changes in cardiac function after i.p. doses of the drug were more variable, although the trend of changes, as after i.v. administration, appeared to be dose-dependent. Recovery of cardiac function occurred at 20 weeks after an i.p. dose of 4 mg/kg; however, after 6 mg/kg, cardiac function was significantly depressed after greater than or equal to 16 weeks. For both routes of administration, the likelihood of late cardiac complications was dependent on the level of the reduction in cardiac output at 12 weeks. A study of the impairment of cardiac output and the incidence of cardiac-related mortality demonstrated that epirubicin was more cardiotoxic after i.v. administration. Equivalent cardiotoxic doses of epirubicin after i.v. and i.p. administration were highly linearly correlated (r = 0.998), although there appeared to be a threshold dose of 3.33 mg/kg after i.p. administration of the drug. Thus, the relative cardiotoxicity between the two routes of administration was found to be dependent on the drug dose and, hence, the level of effect. The difference in the effect was less for high drug doses. The LD50 for deaths due to cardiotoxicity at 20 weeks was 4.42 +/- 0.42 mg/kg after i.v. administration, which was significantly lower than the value of 6.28 +/- 0.41 mg/kg obtained after i.p. administration of the drug (P less than 0.01). There was no qualitative difference in the histological lesions induced in the myocardium after the i.v. vs i.p. administration of epirubicin.
Yeung
T K
TK
CRC Normal Tissue Radiobiology Research Group, University of Oxford, Churchill Hospital, U.K.
Simmonds
R H
RH
Hopewell
J W
JW
D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D002303:Cardiac Output, Low / Q000139:chemically induced / Q000401:mortality / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D015251:Epirubicin / Q000008:administration & dosage / Q000633:toxicity*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007928:Lethal Dose 50; D008297:Male; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D015431:Weight Loss / Q000187:drug effects
D015251:Epirubicin