Comparative metabolism and elimination of adriamycin and 4'-epiadriamycin in the rat

Adriamycin (ADR) and 4'-epiadriamycin (epi-ADR) show comparable biological properties in most in vitro and in vivo test systems. However, in animal studies epi-ADR demonstrates diminished toxicity, especially toward cardiac tissue, compared with ADR. A similar reduction in anthracycline-induced cardiotoxicity with epi-ADR, relative to ADR, is claimed in connection with the clinical evaluation of this agent. The present study was undertaken in an attempt to find a possible pharmacological basis for this observed differential toxicity. Following identical bolus doses (10 mg/kg) of drug administered to rats, no differences were seen in plasma drug levels of the two agents at 4, 7, and 24 h. However, differences in the rate and extent of drug elimination were clearly noted. Thus, following either 24-h infusion or bolus drug administration, parent drugs were eliminated largely in the bile, with the recovery of epi-ADR [50% (infusion) and 40% (bolus) in 54 h and 55 h respectively] exceeding that of ADR [31% (infusion) and 23% (bolus) at the corresponding times]. Recovery of a bolus drug dose in the urine was only 4.8% for epi-ADR vs 3.3% for ADR in 60 h. For each drug the only significant metabolite seen was the corresponding 13-carbinol derivative, adriamycinol (AMNOL) or 4'-epiadriamycinol (epi-AMNOL). The 13-carbinol metabolite represented a larger part of the recovered dose for ADR [15% (infusion) and 18% (bolus) in bile, 0.3% in urine] than for epi-ADR [7% (infusion) and 11% (bolus) in bile, 0.04% in urine]. Epi-ADR was found to be a four fold poorer substrate than ADR for conversion to its 13-carbinol metabolite by aldo-keto reductase enzymes in crude rat liver homogenate preparations. This latter finding provides an explanation for the metabolic and toxicologic differences observed with these agents in whole animals. Previous studies with ADR have reported that degenerative changes in rat cardiac tissue were accompanied by an accumulation of AMNOL during chronic drug administration. Thus, the present study suggests that the reported lower toxicity of epi-ADR compared to ADR for the heart may result from a more extensive elimination of parent drug in bile and urine, as well as diminished metabolic conversion to its 13-carbinol metabolite by ubiquitous aldo-keto reductase enzymes.