Pharmacokinetic-toxicodynamic relationships of adriamycin in rat: prediction of butylated hydroxyanisole-mediated reduction in anthracycline cardiotoxicity.

Abstract

Adriamycin, an anthracycline antibiotic, has broad antitumour activity with cumulative dose-dependent cardiotoxicity as its major side effect. This study was designed to quantify and correlate the cardiotoxicity and pharmacokinetics of adriamycin in-vivo in rat. The influence of antioxidant (butylated hydroxyanisole, BHA) co-therapy on the cardiotoxicity and disposition of adriamycin was also studied. Cardiotoxicity was estimated by serially measuring serum creatine kinase (CK) levels after intravenous administration of adriamycin (4, 10, 20, and 30 mg kg-1) and adriamycin-BHA (10 and 30 mg kg-1 each). Peak serum CK concentrations (CKmax) and area under serum CK-time curves (AUCCK) were used as cardiotoxicity indices. Pharmacokinetic studies were undertaken by sampling plasma and urine from distinct groups of rats treated with [14C]adriamycin (at the above doses) and [14C]adriamycin-BHA (10 mg kg-1 each). Co-administration of BHA resulted in a significant reduction in CKmax and also resulted in a significant reduction in the renal clearance of adriamycin which was fully compensated by an increase in its metabolic clearance. A linear increase in the area under the plasma adriamycin concentration-time curves (AUC) with increasing adriamycin doses suggested dose-independent disposition of the drug. The most significant pharmacokinetic-toxicodynamic relationships included: CKmax = 2.25 x 10(2) exp (4 x 10(-4) AUC), r2 = 0.941, P < 0.05 and AUCCK = 1.3 x 10(4) exp(2 x 10(-4) AUC0-tmax), r2 = 0.918, P < 0.05 where, AUC0-tmax is the area under the adriamycin concentration-time curve from time 0 to the time of the peak CK level. The results strongly indicate that the drug-induced cardiotoxicity is initiated shortly after dosing when drug concentrations are high and accumulates with continued exposure. The predicted cardiotoxic indices, obtained from altered adriamycin pharmacokinetic parameters as a result of BHA co-therapy, compared favourably with the observed values.