Donelli M G, Bartosek I, Guaitani A, Martini A, Colombo T, Pacciarini M A, Modica R
Cancer Treat Rep. 1976 Apr;60(4):395-401.
Pharmacokinetic studies on cyclophosphamide (CP) and its alkylating metabolites produced by hepatic biotransformation have been performed in vivo in animals and in vitro in the perfused liver. CP levels were determined by a gas-chromatographic method combined with mass-spectrometry, and production of alkylating metabolites was assayed by the 4-(4-nitrobenzyl)pyridine reaction for alkylating compounds. Differenes in serum drug levels between normal rats and rats bearing Walker 256 carcinosarcoma were observed in vivo and were confirmed by the liver-perfusion technique. Pharmacokinetic parameters and enzyme kinetic data both in normal and in tumor-bearing animals will be presented. The disappearance of CP and the corresponding formation of CP metabolites was significantly modified when (a) CP was given after previous treatment with a compound which alters its biotransformation (ie, phenobarbital, an inducer of microsomal metabolism), (b) CP was given after previous treatment with CP (which inhibits microsomal metablism), or (c) CP was given with competitive substrates of aldehyde oxidase or dehydrogenase (glyceraldehyde, chloral hydrate, and disulfiram). Results obtained in animals or in the perfused liver will be discussed. The significance of this modified CP metabolism in influencing its cytotoxic effect will be discussed and correlations between drug levels and activity will be presented.
已在动物体内以及在灌注肝脏的体外实验中开展了对环磷酰胺（CP）及其经肝脏生物转化产生的烷基化代谢产物的药代动力学研究。CP水平通过气相色谱法结合质谱法测定，烷基化代谢产物的生成通过针对烷基化化合物的4-（4-硝基苄基）吡啶反应进行测定。在体内观察到正常大鼠与荷Walker 256癌肉瘤大鼠之间血清药物水平存在差异，并通过肝脏灌注技术得到证实。将呈现正常动物和荷瘤动物的药代动力学参数及酶动力学数据。当出现以下情况时，CP的消失及其相应代谢产物的形成会发生显著改变：（a）在用改变其生物转化的化合物（即苯巴比妥，微粒体代谢诱导剂）预先处理后给予CP；（b）在用CP预先处理后给予CP（CP抑制微粒体代谢）；或（c）CP与醛氧化酶或脱氢酶的竞争性底物（甘油醛、水合氯醛和双硫仑）同时给予。将讨论在动物或灌注肝脏中获得的结果。将讨论这种改变的CP代谢对其细胞毒性作用的影响的意义，并呈现药物水平与活性之间的相关性。
