Doxorubicin toxicity and pharmacokinetics in old and young rats

Abstract

Doxorubicin (Dx) toxicity was compared in old (24 months) and young (6 weeks) Crl:CD(SD) BR male rats, and a clear age-related increase was found. The mortality of all animals receiving a single i.v. Dx dose was followed for 270 days. Old rats died after doses of 2.5 mg/kg, while young animals died after doses two times higher, 5 mg/kg. In old rats body weight loss started 10 to 15 days after Dx, compared to 50 to 80 days for young animals. In young and old rats pharmacokinetic and metabolic studies of Dx were conducted in vivo and in the liver perfusion model. Peak levels of Dx and areas under the time/concentration curves (AUC) in serum and in several tissues of old rats were 1.5 to 2 times higher than in young rats. Concentrations of Dx metabolites in serum and tissues (doxorubicinol, Dxol, and doxorubicinone, Dxone) in young and old rats were not noteworthy. However, higher percentages of Dxone than Dxol were found in both groups in vivo and in vitro. Old livers appeared to produce more Dxone as a percentage, particularly in the bile, which was higher. Urinary elimination of Dx markedly slowed with age; only small amounts of the metabolites were eliminated in urine. In vivo and in vitro availability of Dx and its metabolites is discussed in view of their possible role in the greater toxicity observed in 24-month-old rats.