Hartman N, Basseches P J, Powis G
Cancer Chemother Pharmacol. 1982 Dec;10(1):11-5. doi: 10.1007/BF00257229.
The effect of pretreatment with cyclophosphamide 180 mg/kg upon the short-term disposition of adriamycin in anesthetized rat 4 days later was studied. There was a significant decrease in plasma adriamycin clearance, from 125 to 48 ml/min/kg, and a significant decrease in the apparent volume of the peripheral compartment of adriamycin distribution, from 51.7 to 25.6 l/kg, in cyclophosphamide-pretreated as against control rats. Biliary excretion of adriamycin over 2.5 h was increased significantly by 114% in cyclophosphamide-pretreated rats and there was a small but nonsignificant increase in biliary adriamycinol excretion and a decrease in excretion of adriamycin aglycones. Cyclophosphamide pretreatment was associated with an 83% increase in bile flow. Cyclophosphamide pretreatment had no significant effect upon the utilization of adriamycin or upon the formation of adriamycin metabolites by rat isolated hepatocytes. The results suggest that NADPH-cytochrome P-450 reductase, which is decreased 40% by cyclophosphamide pretreatment, is not rate-limiting in elimination of adriamycin. Biliary excretion of adriamycin is increased when plasma adriamycin clearance is decreased, suggesting that cyclophosphamide pretreatment affects a pathway besides biliary excretion that is responsible for the short-term removal of adriamycin from plasma.
研究了180mg/kg环磷酰胺预处理对4天后麻醉大鼠阿霉素短期处置的影响。与对照大鼠相比，环磷酰胺预处理的大鼠血浆阿霉素清除率显著降低，从125ml/min/kg降至48ml/min/kg，阿霉素分布外周室的表观容积也显著降低，从51.7l/kg降至25.6l/kg。环磷酰胺预处理的大鼠2.5小时内阿霉素的胆汁排泄显著增加了114%，阿霉素醇的胆汁排泄有小幅但不显著的增加，阿霉素苷元的排泄减少。环磷酰胺预处理使胆汁流量增加了83%。环磷酰胺预处理对大鼠离体肝细胞对阿霉素的利用或阿霉素代谢产物的形成没有显著影响。结果表明，环磷酰胺预处理使NADPH-细胞色素P-450还原酶降低40%，但该酶在阿霉素消除过程中并非限速酶。当血浆阿霉素清除率降低时，阿霉素的胆汁排泄增加，这表明环磷酰胺预处理除了影响胆汁排泄途径外，还影响了另一条负责从血浆中短期清除阿霉素的途径。
