Ren S, Kalhorn T F, McDonald G B, Anasetti C, Appelbaum F R, Slattery J T
Department of Pharmaceutics, University of Washington, Seattle, USA.
Clin Pharmacol Ther. 1998 Sep;64(3):289-301. doi: 10.1016/S0009-9236(98)90178-3.
To characterize the pharmacokinetics of cyclophosphamide and 5 of its metabolites in bone marrow transplant patients and to identify the mechanism of the increase in 4-hydroxycyclophosphamide area under the plasma concentration-time curve (AUC) from day 1 to day 2 of cyclophosphamide administration.
Cyclophosphamide was administered by intravenous infusion (60 mg/kg over 1 hour, once a day) for 2 consecutive days to 18 patients. Cyclophosphamide and 4-hydroxycyclophosphamide concentration time data on day 1 and day 2 were fitted to a model to estimate 4-hydroxycyclophosphamide formation (CLf) and elimination (CLm) clearances. Erythrocyte aldehyde dehydrogenase-1 activity was measured ex vivo just before the first cyclophosphamide infusion was started (0 hours) and 24 hours after the second cyclophosphamide infusion (48 hours).
From day 1 to day 2, the AUC of cyclophosphamide, deschloroethyl cyclophosphamide and phosphoramide mustard decreased 24.8%, 51%, and 29.4% (P < .02), the AUC of 4-hydroxycyclophosphamide and carboxyethylphosphoramide mustard increased 54.7% and 25% (P < .01), whereas the AUC of phosphoramide mustard was not significantly changed (P > .3). The CLf of 4-hydroxycyclophosphamide increased 60% (P < .001), its CLm decreased 27.7% (P < .001), and the fraction of cyclophosphamide dose converted to 4-hydroxycyclophosphamide increased 16% (P < .001) from day 1 to day 2. The activity of patient erythrocyte aldehyde dehydrogenase-1 decreased 23.3% (P < .02) from 0 hours to 48 hours.
The AUC of 4-hydroxycyclophosphamide increased from day 1 to day 2 as a result of increased formation and decreased elimination clearances of 4-hydroxycyclophosphamide. Aldehyde dehydrogenase-1 activity appears to decline as a consequence of cyclophosphamide administration.
描述环磷酰胺及其5种代谢产物在骨髓移植患者中的药代动力学特征，并确定环磷酰胺给药第1天至第2天血浆浓度-时间曲线下4-羟基环磷酰胺面积增加的机制。
对18例患者连续2天静脉输注环磷酰胺（60mg/kg，1小时内输完，每天1次）。将第1天和第2天的环磷酰胺和4-羟基环磷酰胺浓度-时间数据拟合到一个模型中，以估计4-羟基环磷酰胺的生成（CLf）和消除（CLm）清除率。在首次环磷酰胺输注开始前（0小时）和第二次环磷酰胺输注后24小时（48小时）离体测量红细胞醛脱氢酶-1活性。
从第1天到第2天，环磷酰胺、去氯乙基环磷酰胺和磷酰胺氮芥的AUC分别下降了24.8%、51%和29.4%（P<.02），4-羟基环磷酰胺和羧乙基磷酰胺氮芥的AUC分别增加了54.7%和25%（P<.01），而磷酰胺氮芥的AUC没有显著变化（P>.3）。从第1天到第2天，4-羟基环磷酰胺的CLf增加了60%（P<.001），其CLm下降了27.7%（P<.001），环磷酰胺剂量转化为4-羟基环磷酰胺的比例增加了16%（P<.001）。患者红细胞醛脱氢酶-1活性从0小时到48小时下降了23.3%（P<.02）。
4-羟基环磷酰胺的AUC从第1天到第2天增加，是由于4-羟基环磷酰胺生成增加和消除清除率降低所致。醛脱氢酶-1活性似乎因环磷酰胺给药而下降。
