A study of doxorubicin toxicity

Grewal, Kuldip (1987) A study of doxorubicin toxicity. Masters thesis, Memorial University of Newfoundland.

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Abstract

We examined myocardial injury following Doxorubicin use via analysis with the Automated Hitachi Analyzer of serum activity changes of enzymes specific for myocardial tissue. Sprague-Dawley rats were administered either saline, 3, 6, or 9 mg/kg doses of Doxorubicin by intraperitoneal injection. Blood samples were collected at times 0 and 48 hours posttreatment. There was an increase in serum creatine kinase (except the 9 mg/kg injected rats), lactate dehydrogenase (LD), including elevations of LD 1 and LD 2 isoenzymes and aspartate aminotransferase (AST)activities at 48 hours post Doxorubicin injection. Increasing drug dosage resulted in increasing myocardial tissue concentration of the drug as measured by high performance liquid chromatography. This suggests increasing Doxorubicin dosage leads to increased myocardial tissue concentration of drug and is associated with tissue damage and release of cardiac-specific enzymes. -- Serum CK isoenzyme separation by electrophoresis revealed the presence of an additional band cathodic to CK-MM following administration of 6 and 9 mg/kg doses of the drug. Creatine kinase isoenzyme analysis of mitochondria also demonstrated this band in a position corresponding to that observed in the drug-treated animals. We suggest that at these doses mitochondrial damage resulted in the release of mitochondrial CK. -- At a drug dose of 9 mg/kg, increased serum alanine aminotransferase (ALT) and LD 4 and LD 5 isoenzymes was observed suggesting hepatotoxicity. -- In rats, 24 hour urine specimens were analyzed for various biochemical parameters with the use of the Automated Hitachi Analyzer, the Astra-8 Automated Analyzer and the Chemstrip 9 Dipstick screen test, to detect evidence of renal damage. The only abnormality noted was a decreased urine volume with increased dose of the drug. -- In the New Zealand white rabbit model, we demonstrated a serum CK-MB activity greater than five percent of total CK activity in all rabbits 48 hours subsequent to treatment with 10 mg/kg Doxorubicin. There was no such effect in the saline-treated controls. Myoglobin was detected in the serum 48 hours following a 10 mg/kg dose using the Rapitex Myoglobin kit. The origin of CK-MB was believed to be cardiac muscle; however the source of myoglobin could have been either skeletal muscle or myocardium.

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