Contradistinction between doxorubicin and epirubicin: in-vivo metabolism, pharmacokinetics and toxicodynamics after single- and multiple-dosing in rats

• Published in: Journal of pharmacy and pharmacology 2001-07, Vol.53 (7), p.987-997
• Main Authors: Ramanathan-Girish, Sandhya, Boroujerdi, Mehdi
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - blood; Antibiotics, Antineoplastic - toxicity; Antibiotics, Antineoplastic - urine; Antineoplastic agents; Bile - metabolism; Biological and medical sciences; Calcium-Transporting ATPases - metabolism; Dose-Response Relationship, Drug; Doxorubicin - administration & dosage; Doxorubicin - blood; Doxorubicin - toxicity; Doxorubicin - urine; Drug Administration Schedule; Epirubicin - administration & dosage; Epirubicin - blood; Epirubicin - toxicity; Epirubicin - urine; General aspects; Injections, Intravenous; Male; Medical sciences; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Sarcoplasmic Reticulum - drug effects; Sarcoplasmic Reticulum - enzymology; Sarcoplasmic Reticulum Calcium-Transporting ATPases
• ISSN: 0022-3573; 2042-7158
• DOI: 10.1211/0022357011776234

There is compelling in‐vitro evidence that the evaluation of doxorubicin or epirubicin pharmacokinetics based solely on plasma concentration may not fully elucidate the differences between the two drugs. Both compounds bind to erythrocytes and their different binding to haemoglobin may influence their disposition in the body. The purpose of the present study was to compare the pharmacokinetics and metabolism of doxorubicin and epirubicin based on the plasma concentration, amount associated with blood cells and simultaneous monitoring of biliary and urinary elimination of unchanged drug and metabolites after single‐ and multiple‐dose injections. The level of sarcoplasmic reticulum Ca2+ ATPase in the heart was also measured as a biomarker of cardiotoxicity. Male Sprague‐Dawley rats were treated in a parallel design with doxorubicin or epirubicin on a multiple‐dosing basis (4 mg kg−1 per week) or as a single dose injection (20 mg kg−1). Blood, urine and bile samples were collected periodically after each dose in the multiple‐dosing regimen and the single dose injection, and at the end of each experiment the hearts were removed. The concentrations of each drug in plasma, blood cells, bile and urine samples were determined, and by simultaneous curve‐fitting of plasma and bile data according to compartmental analysis, the pharmacokinetic parameters and constants were estimated. The concentration of drug associated with blood cells was analysed according to non‐compartmental analysis. The bile and urine samples provided the in‐vivo metabolic data. The level of Ca2+ ATPase in the heart, determined by Western blotting, was used as the toxicodynamic parameter to correlate with the kinetic data. Multiple‐dosing regimens reduced the total plasma clearance and increased the area under the plasma concentration‐time curve of both drugs. Also, the area under the curve of doxorubicin associated with blood cells increased with the weekly doses, and the related mean residence time (MRT) and apparent volume of distribution (Vdss) were steadily reduced. In contrast to doxorubicin, the MRT and Vdss of epirubicin increased significantly. Metabolic data indicated significant differences in the level of alcohol and aglycones metabolites. Doxorubicinol and doxorubicin aglycones were significantly greater than epirubicinol and epirubicin aglycone, whereas epirubicinol aglycone was greater than doxorubicinol aglycone. The area under the blood cells concentration‐time curve correlated