Sladek N E, Powers J F, Grage G M
Drug Metab Dispos. 1984 Sep-Oct;12(5):553-9.
Plasma AUC and half-life values for cyclophosphamide were determined in rats manipulated to hydroxylate cyclophosphamide at different rates; plasma AUC and apparent half-life values for two pharmacologically important metabolites of cyclophosphamide, viz. 4-hydroxycyclophosphamide/aldophosphamide and phosphoramide mustard, were also determined in these animals. Apparent plasma half-life values for 4-hydroxycyclophosphamide/aldophosphamide and phosphoramide mustard increased with an increase in plasma half-life values for cyclophosphamide. AUC values for cyclophosphamide increased approximately linearly with an increase in its plasma half-life but AUC values for 4-hydroxycyclophosphamide/aldophosphamide and phosphoramide mustard remained approximately constant with an increase in their respective apparent plasma half-life values. Given that the cytotoxic effects of cyclophosphamide are directly proportional to AUC values for 4-hydroxycyclophosphamide/aldophosphamide and/or phosphoramide mustard, we conclude that changes in the rate of cyclophosphamide hydroxylation will not alter the systemic toxic and therapeutic responses to a given dose of cyclophosphamide. Actual half-life values for 4-hydroxycyclophosphamide/aldophosphamide and phosphoramide mustard after the iv infusion of these agents were also determined. A comparison of the actual plasma half-life values for cyclophosphamide (29 min), 4-hydroxycyclophosphamide/aldophosphamide (14 min), and phosphoramide mustard (14 min) with the apparent plasma half-life values obtained for 4-hydroxycyclophosphamide/aldophosphamide (34 min) and phosphoramide mustard (55 min) following cyclophosphamide administration suggests that the major determinant with regard to the apparent plasma half-life of 4-hydroxycyclophosphamide/aldophosphamide is its rate of formation whereas in the case of phosphoramide mustard, an additional determinant, perhaps efflux from the cell, is operative.(ABSTRACT TRUNCATED AT 250 WORDS)
在以不同速率操纵环磷酰胺羟化的大鼠中测定了环磷酰胺的血浆药时曲线下面积（AUC）和半衰期值；还在这些动物中测定了环磷酰胺的两种具有药理学重要性的代谢物，即4-羟基环磷酰胺/醛磷酰胺和磷酰胺氮芥的血浆AUC和表观半衰期值。4-羟基环磷酰胺/醛磷酰胺和磷酰胺氮芥的表观血浆半衰期值随环磷酰胺血浆半衰期值的增加而增加。环磷酰胺的AUC值随其血浆半衰期的增加大致呈线性增加，但4-羟基环磷酰胺/醛磷酰胺和磷酰胺氮芥的AUC值随其各自表观血浆半衰期值的增加大致保持恒定。鉴于环磷酰胺的细胞毒性作用与4-羟基环磷酰胺/醛磷酰胺和/或磷酰胺氮芥的AUC值直接相关，我们得出结论，环磷酰胺羟化速率的变化不会改变对给定剂量环磷酰胺的全身毒性和治疗反应。还测定了静脉输注这些药物后4-羟基环磷酰胺/醛磷酰胺和磷酰胺氮芥的实际半衰期值。将环磷酰胺（29分钟）、4-羟基环磷酰胺/醛磷酰胺（14分钟）和磷酰胺氮芥（14分钟）的实际血浆半衰期值与环磷酰胺给药后4-羟基环磷酰胺/醛磷酰胺（34分钟）和磷酰胺氮芥（55分钟）获得的表观血浆半衰期值进行比较表明，关于4-羟基环磷酰胺/醛磷酰胺表观血浆半衰期的主要决定因素是其形成速率，而对于磷酰胺氮芥，一个额外的决定因素，可能是从细胞中的流出，起作用。（摘要截断于250字）
