New aspects in probucol cardioprotection against doxorubicin-induced cardiotoxicity.
OBJECTIVE
Doxorubicin (DOX) is a broad-spectrum anticancer drug with dose-dependent cardiotoxicity. Probucol has been reported to completely prevent DOX-induced cardiomyopathy. The aim of the present study was to determine the possible effect of probucol pretreatment on the pharmacokinetics of DOX and its role in cardioprotection as well as the possible contribution of the lipid-lowering effect of probucol on the disposition of DOX in cardiac tissue.


METHODS
Two groups of male albino rats were given either probucol (10 mg/kg, i.p.) or corn oil daily for 12 days followed by a single dose of DOX (15 mg/kg, i.p.). The concentration-time profile of DOX in plasma and its concentration in different tissues, and plasma and myocardial lipids were determined.


RESULTS
A rapid and significant increase in plasma DOX clearance was observed in rats pretreated with probucol. Probucol induced a significant increase in DOX concentration in both liver and kidney tissues and a significant decrease in DOX concentration in the spleen. However, heart and lung DOX concentrations were not affected. Also, probucol pretreatment resulted in a significant reduction in cardiotoxicity indices including peak serum creatine kinase (CK) concentration and the area under the CK concentration-time curve. Moreover, probucol pretreatment not only counteracted significantly the decrease in the ATP/ADP ratio induced by DOX, but also induced a significant increase as compared with the control group. In addition, probucol significantly reduced plasma total cholesterol and low-density lipoprotein, but it did not induce any significant changes in myocardial lipids.


CONCLUSIONS
The present study demonstrated, for the first time, that probucol pretreatment alters the pharmacokinetics of DOX. Besides its antioxidant properties, the cardioprotective effect of probucol may be related to its enhancing action on the ATP/ADP ratio.
El-Demerdash
Ebtehal
E
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Ali
Azza A
AA
Sayed-Ahmed
Mohamed M
MM
Osman
Abdel-Moneim M
AM
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000633:toxicity*; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D002784:Cholesterol / Q000378:metabolism; D003402:Creatine Kinase / Q000097:blood; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000633:toxicity*; D006207:Half-Life; D006331:Heart Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009711:Nucleotides / Q000378:metabolism; D011341:Probucol / Q000627:therapeutic use*; D051381:Rats
D000903:Antibiotics, Antineoplastic; D000924:Anticholesteremic Agents; D008055:Lipids; D009711:Nucleotides; D000244:Adenosine Diphosphate; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D002784:Cholesterol; D003402:Creatine Kinase; D011341:Probucol