Behnia K, Boroujerdi M
Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
J Pharm Pharmacol. 1999 Nov;51(11):1275-82. doi: 10.1211/0022357991777010.
Doxorubicin is an effective anticancer agent that is limited by numerous adverse effects, cardiotoxicity causing the most concern. Its alcohol metabolite, doxorubicinol, and free radicals have been implicated in the aetiology of this toxicity. This study was based on the premise that inhibition of aldo-keto reductases would improve the efficacy of doxorubicin by reducing its toxic metabolites and modifying its pharmacokinetics. We assessed the effect of in-vitro inhibition of aldo-keto reductases on the metabolism of doxorubicin in cytosolic fractions of heart and liver of rats in the presence of Na-phenobarbital. The inhibition was confirmed by a significant reduction in the formation of doxorubicinol. The results of the in-vitro study were further evaluated in-vivo. The concentrations of doxorubicin in plasma, bile and urine and its major metabolites in bile and urine were measured in Na-phenobarbital-pretreated rats. Each rat received 100 mg kg(-1)/day intraperitoneal injection of sodium phenobarbital for three days followed by a single intravenous dose of 10 mg kg(-1) [14C-14]doxorubicin (sp. act. 0.2 microCi mg(-1)) on the fourth day. The levels of drug in all biological samples were measured by HPLC. The pretreatment resulted in an increase in biological half-life (5.8 +/- 1.5 vs 3.7 +/- 0.93 h control group, P < 0.05) and area under plasma concentration-time curve (19.6 +/- 1.7 vs 14.65 +/- 1.68 mg h L(-1) control group, P < 0.05). The cumulative amount of doxorubicinol in the bile and urine of pretreated animals was reduced significantly. In terms of % dose, the amount in the bile declined from 4.2 +/- 0.8% in control to 2.4 +/- 0.3% and in urine from 0.18 +/- 0.08% to 0.12 +/- 0.07%. There were no significant changes in doxorubicin aglycone and doxorubicinol aglycone. Serum creatine kinase levels were measured as a biomarker of damage to cardiac muscle. The area under creatine kinase level-time curve was reduced by approximately 50% in phenobarbital-pretreated animals. The results indicate that the inhibition of aldo-keto reductase could provide a useful approach to improve the safety of doxorubicin by reducing its alcohol metabolite. Furthermore, if the reduction in the area under the serum creatine kinase-time curve represents a reduced damage to heart muscle, it can be concluded that doxorubicinol plays an important role in this injury.
阿霉素是一种有效的抗癌药物，但因众多不良反应而受到限制，其中心脏毒性最令人担忧。其醇代谢产物阿霉素醇和自由基被认为与这种毒性的病因有关。本研究基于这样一个前提，即抑制醛糖还原酶可通过减少其有毒代谢产物并改变其药代动力学来提高阿霉素的疗效。我们评估了在苯巴比妥存在的情况下，体外抑制醛糖还原酶对大鼠心脏和肝脏胞质部分中阿霉素代谢的影响。通过阿霉素醇形成的显著减少证实了这种抑制作用。体外研究的结果在体内进一步评估。在苯巴比妥预处理的大鼠中测量了血浆、胆汁和尿液中阿霉素的浓度及其在胆汁和尿液中的主要代谢产物。每只大鼠连续三天腹腔注射100 mg kg(-1)/天的苯巴比妥钠，然后在第四天静脉注射单次剂量10 mg kg(-1)的[14C-14]阿霉素（比活度0.2微居里毫克(-1)）。通过高效液相色谱法测量所有生物样品中的药物水平。预处理导致生物半衰期增加（5.8 +/- 1.5对对照组的3.7 +/- 0.93小时，P < 0.05）以及血浆浓度-时间曲线下面积增加（19.6 +/- 1.7对对照组的14.65 +/- 1.68毫克小时L(-1)，P < 0.05）。预处理动物胆汁和尿液中阿霉素醇的累积量显著减少。以剂量百分比计，胆汁中的量从对照组的4.2 +/- 0.8%降至2.4 +/- 0.3%，尿液中的量从0.18 +/- 0.08%降至0.12 +/- 0.07%。阿霉素苷元和阿霉素醇苷元没有显著变化。测量血清肌酸激酶水平作为心肌损伤的生物标志物。在苯巴比妥预处理的动物中，肌酸激酶水平-时间曲线下面积减少了约50%。结果表明，抑制醛糖还原酶可能是一种通过减少其醇代谢产物来提高阿霉素安全性的有用方法。此外，如果血清肌酸激酶-时间曲线下面积的减少代表心肌损伤的减轻，可以得出结论，阿霉素醇在这种损伤中起重要作用。
