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New aspects in probucol cardioprotection against doxorubicin-induced cardiotoxicity

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Abstract

Purpose

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.

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References

  1. Behnia K, Boroujerdi M (1999) Inhibition of aldo-keto reductase by phenobarbital alters metabolism, pharmacokinetics and toxicity of doxorubicin in rats. J Pharm Pharmacol 51:1275

    Google Scholar 

  2. Bridges AB, Scott NA, Blech JJF (1991) Probucol, a superoxide free radical scavenger in-vitro. Atherosclerosis 89:263

    Google Scholar 

  3. Bucolo G, David H (1973) Quantitative determination of serum triglycerides by the use of enzymes. Clin Chem 19:476

    Google Scholar 

  4. Dawson DM, Eppenberger HM, Kaplan NO (1965) Creatine kinase: evidence for a dimeric structure. Biochem Biophys Res Commun 21:346

    Google Scholar 

  5. Eksborg S, Stendahl U, Lonroth U (1986) Comparative pharmacokinetic study of adriamycin and 4′-epiadriamycin after their simultaneous intravenous administration. Eur J Clin Pharmacol 30:629

    Google Scholar 

  6. Formelli F, Pollini C, Carazza AM, DiMarco A, Mariani A (1981) Fluorescence assays and pharmacokinetic studies of 4′-deoxydoxorubicin and doxorubicin in organs of mice bearing solid tumors. Cancer Chemother Pharmacol 5:139

    Google Scholar 

  7. Geetha A, Sankar R, Marar T, Devi CSS (1990) α-tocopherol reduces doxorubicin-induced toxicity in rats: histological and biochemical evidences. Indian J Physiol Pharmacol 34:94

    Google Scholar 

  8. Li T, Singal PK (2000) Adriamycin-induced early changes in myocardial antioxidant enzymes and their modulation by probucol. Circulation 102:2105

    Google Scholar 

  9. Lliskovic N, Singal PK (1997) Lipid lowering: an important factor in preventing adriamycin-induced heart failure. Am J Pathol 150:727

    Google Scholar 

  10. Mason RP (1993) Membrane interaction of calcium channel antagonists modulated by cholesterol: implication for drug activity. Biochem Pharmacol 45:2173

    Google Scholar 

  11. McHowat J, Swift LM, Arutunyan A, Sarvazyan N (2001) Clinical concentrations of doxorubicin inhibit activity of myocardial membrane-associated calcium dependent phospholipase A2. Cancer Res 61:4024

    Google Scholar 

  12. Modi KS, Morrissey J, Shah SV, Schreiner GF, Klahr S (1990) Effects of probucol on renal function in rats with bilateral ureteral obstruction. Kidney Int 38:843

    Google Scholar 

  13. Muhammed H, Ramasarma T, Kurup CKR (1983) Inhibition of mitochondrial oxidative phosphorylation by adriamycin. Biochim Biophys Acta 722:43

    Google Scholar 

  14. Myers CE (1992) Anthracyclines. In: Pinedo HM, Longo DL, Chabner BA (eds) Cancer chemotherapy and biological modifiers (annual 13). Elsevier, New York, p 45

  15. Neri B, Cini-Neri G, Bartalucci S, Bandinelli M (1986) Protective effect of L-carnitine on cardiac metabolic damage induced by doxorubicin in vivo. Anticancer Res 6:659

    Google Scholar 

  16. Norlen P, Kitano M, Lindstrom E, Hakanson R (2000) Anaesthetic agents inhibit gastrin-stimulated but not basal histamine release from rat stomach ECL cells. Br J Pharmacol 130:725

    Google Scholar 

  17. Powis G (1991) Toxicity of free radical forming anticancer drugs. In: Powis G, Hacker MP (eds) The toxicity of anticancer drugs. Pergamon, New York, p 106

  18. Preus M, Bhargava AS, Khater AER, Gunzel P (1988) Diagnostic value of serum creatine kinase and lactate dehydrogenase isoenzyme determinations for monitoring early cardiac damage in rats. Toxicol Lett 42:225

    Google Scholar 

  19. Ramanathan-Girish S, Boroujerdi M (2001) Contradistinction between doxorubicin and epirubicin: in-vivo metabolism, pharmacokinetics and toxicodynamics after single- and multiple-dosing in rats. J Pharm Pharmacol 53:987

    Google Scholar 

  20. Rhaman M, Carmichael D, Harris M, Roh JK (1986) Comparative pharmacokinetics of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes. Cancer Res 46:2295

    Google Scholar 

  21. Richmond W (1973) Preparation and properties of a cholesterol oxidase from Nocardia sp. and its application to the enzymatic assay of total cholesterol in serum. Clin Chem 19:1350

    Google Scholar 

  22. Ritschel WA (1976) Handbook of basic pharmacokinetics. Drug Intelligence Publications, Hamilton, IL, p 210

  23. Scheulen ME, Kappus H (1992) Anthracyclines as model compounds for cardiac toxicity. In: Dekant W, Neumann HG (eds) Tissue specific toxicity: biochemical mechanisms. Academic Press, New York, p 221

  24. Seymour LW, Ulbrich K, Strohalm J, Kopecek J, Duncan R (1990) The pharmacokinetics of polymer-bound adriamycin. Biochem Pharmacol 39:1125

    Google Scholar 

  25. Sia YT, Lapointe N, Parker TG, Tsoporis JN, Deschepper CF, Calderone A, Pourdjabbar A, Jasmin JF, Sarrazin JF, Liu P, Adam A, Butany J, Rouleau JL (2002) Beneficial effects of long-term use of the antioxidant probucol in heart failure in the rat. Circulation 105:2549

    Google Scholar 

  26. Sia YT, Parke TG, Liu P, Tsoporis JN, Adam A, Rouleau JL (2002) improved post-myocardial infarction survival with probucol in rats: effects on left ventricular function, morphology, cardiac oxidative stress and cytokine expression. J Am Coll Cardiol 39:148

    Google Scholar 

  27. Siveski-lliskovic N, Kaul N, Singal PK (1994) Probucol promotes endogenous antioxidants and provides protection against adriamycin-induced cardiomyopathy in rats. Circulation 89:2829

    Google Scholar 

  28. Siveski-lliskovic N, Hill M, Chow D, Singal PK (1995) Probucol protects against adriamycin cardiomyopathy without interfering with its antitumor properties. Circulation 91:10

    Google Scholar 

  29. Smith IE (1985) Optimal schedule for anthracyclines. Eur J Cancer Clin Oncol 21:159

    Google Scholar 

  30. Sternberg SS, Philips FS, Cronin AP (1972) Renal tumors and other lesions in rats following a single intravenous injection of daunomycin. Cancer Res 32:1029

    Google Scholar 

  31. Vaidyanathan S, Boroujerdi M (2000) Effect of tamoxifen pretreatment on the pharmacokinetics, metabolism and cardiotoxicity of doxorubicin in female rats. Cancer Chemother Pharmacol 46:185

    Google Scholar 

  32. Vora J, Boroujerdi M (1996) Pharmacokinetic-toxicodynamic relationships of adriamycin in rat: prediction of butylated hydroxyanisole-mediated reduction in anthracyclin cardiotoxicity. J Pharm Pharmacol 48:1264

    Google Scholar 

  33. Vora J, Khaw B, Narula J, Boroujerdi M (1996) Protective effect of butylated hydroxyanisole on adriamycin-induced cardiotoxicity. J Pharm Pharmacol 48:940

    Google Scholar 

  34. Zimetbaum P, Eder H, Frishman W (1990) Probucol: pharmacology and clinical application. J Clin Pharmacol 30:3

    Google Scholar 

  35. Zou Y, Ling YH, Van NT, Priebe W, Perez-Soler R (1994) Antitumor activity of free and liposome-entrapped adriamycin, a lipophilic anthracycline antibiotic with noncross-resistance properties. Cancer Res 54:1479

    Google Scholar 

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Correspondence to Abdel-Moneim M. Osman.

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El-Demerdash, E., Ali, A.A., Sayed-Ahmed, M.M. et al. New aspects in probucol cardioprotection against doxorubicin-induced cardiotoxicity. Cancer Chemother Pharmacol 52, 411–416 (2003). https://doi.org/10.1007/s00280-003-0676-y

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  • DOI: https://doi.org/10.1007/s00280-003-0676-y

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