Vora J, Boroujerdi M
Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
J Pharm Pharmacol. 1996 Dec;48(12):1264-9. doi: 10.1111/j.2042-7158.1996.tb03934.x.
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.
阿霉素是一种蒽环类抗生素，具有广泛的抗肿瘤活性，其主要副作用是累积剂量依赖性心脏毒性。本研究旨在对大鼠体内阿霉素的心脏毒性和药代动力学进行量化并建立相关性。同时还研究了抗氧化剂（丁基羟基茴香醚，BHA）联合治疗对阿霉素心脏毒性和处置的影响。通过静脉注射阿霉素（4、10、20和30 mg kg-1）以及阿霉素-BHA（各10和30 mg kg-1）后连续测量血清肌酸激酶（CK）水平来评估心脏毒性。血清CK峰值浓度（CKmax）和血清CK-时间曲线下面积（AUCCK）用作心脏毒性指标。通过从用[14C]阿霉素（上述剂量）和[14C]阿霉素-BHA（各10 mg kg-1）处理的不同组大鼠中采集血浆和尿液进行药代动力学研究。BHA的联合给药导致CKmax显著降低，同时也导致阿霉素的肾清除率显著降低，而其代谢清除率的增加完全补偿了这一降低。随着阿霉素剂量增加，血浆阿霉素浓度-时间曲线下面积（AUC）呈线性增加，表明该药物的处置与剂量无关。最显著的药代动力学-药效学关系包括：CKmax = 2.25 x 10(2) exp (4 x 10(-4) AUC)，r2 = 0.941，P < 0.05以及AUCCK = 1.3 x 10(4) exp(2 x 10(-4) AUC0-tmax)，r2 = 0.918，P < 0.05，其中，AUC0-tmax是从时间0到CK峰值水平时阿霉素浓度-时间曲线下的面积。结果强烈表明，药物诱导的心脏毒性在给药后不久药物浓度较高时就开始，并随着持续暴露而累积。通过BHA联合治疗改变阿霉素药代动力学参数获得的预测心脏毒性指标与观察值相比具有良好的一致性。
