Voelcker G, Wagner T, Wientzek C, Hohorst H J
Cancer. 1984 Sep 15;54(6 Suppl):1179-86. doi: 10.1002/1097-0142(19840915)54:1+<1179::aid-cncr2820541315>3.0.co;2-p.
Estimation of "activated" cyclophosphamide (4-OH-CP) in blood of cancer patients and laboratory animals has revealed significant differences between pharmacokinetics of cyclophosphamide (CP) in man and laboratory animals after CP treatment. Whereas in blood of mice and rats relatively high concentrations of 4-OH-CP were found to exist for a relatively short time, in blood of humans only low, but longer-lasting, blood levels were detected after administration of comparable CP doses. In order to examine whether these different pharmacokinetic behaviors might account at least in part for the known differences of antitumor activity and toxicity of CP between humans and laboratory animals, the authors studied the influence of pharmacokinetics of activated CP on therapeutic efficacy and toxicity after injection of 4-(S-ethanol)-sulfido-cyclophosphamide (P1), a pro drug of activated CP, into nude mice bearing heterotransplanted human bladder sarcoma. With P1, which hydrolyzes quickly in blood to yield 4-OH-CP, different blood level shapes of 4-OH-CP could be established either by single bolus injection of P1 or by repetitive injection of a loading dose followed by several maintenance doses which caused nearly constant levels of activated CP for a longer time period. With these models it was found that 4-OH-CP showed more therapeutic efficacy when present in blood at relatively low levels for longer times than after bolus injection of the same dose resulting in a sharp peak level of activated CP. So after single intraperitoneal (IP) injection of 300 mg/kg P1 which caused a bioavailability of 36 mumol/ml-1/minute a 67% inhibition of tumor growth was achieved, whereas a tumor growth reduction of 83% was obtained after injection of the same dose in 6 fractions resulting in constant blood levels with a bioavailability of only 17 mumol/ml-1/minute. In contrast to the significant influence on antitumor efficacy of activated CP, practically no effect of pharmacokinetics on toxicity of 4-OH-CP could be observed. Therefore, the bioavailability of activated CP, which killed 50% of the animals, was determined to be approximately 89 mumol/ml-1/minute after adjustment of pharmacokinetics to yield constant levels and approximately 79 mumol/ml-1/minute after single bolus injection. The experiments presented show that by adjustment of pharmacokinetics the therapeutic index of P1, defined as bioavailability causing 50% of animals to die, referred to bioavailability causing 90% tumor growth inhibition, could be more than doubled.
对癌症患者和实验动物血液中“活化”环磷酰胺（4-羟基环磷酰胺，4-OH-CP）的评估显示，环磷酰胺（CP）治疗后，人体和实验动物中环磷酰胺的药代动力学存在显著差异。在小鼠和大鼠血液中，4-OH-CP浓度相对较高，但存在时间较短；而在人类血液中，给予相当剂量的CP后，仅检测到较低但持续时间更长的血药浓度。为了研究这些不同的药代动力学行为是否至少部分解释了已知的CP在人类和实验动物中抗肿瘤活性和毒性的差异，作者研究了活化CP的药代动力学对携带异种移植人膀胱肉瘤的裸鼠注射4-（S-乙醇）-硫代环磷酰胺（P1，活化CP的前体药物）后治疗效果和毒性的影响。P1在血液中迅速水解产生4-OH-CP，通过单次推注P1或重复注射负荷剂量后再注射几次维持剂量，可以建立不同的4-OH-CP血药浓度曲线，后者可使活化CP在较长时间内保持几乎恒定的水平。通过这些模型发现，与单次推注相同剂量导致活化CP血药浓度急剧峰值相比，4-OH-CP在血液中以相对较低水平存在较长时间时显示出更高的治疗效果。因此，单次腹腔注射300mg/kg P1导致生物利用度为36μmol/ml-1/分钟时，肿瘤生长抑制率为67%；而将相同剂量分6次注射，使血药浓度保持恒定，生物利用度仅为17μmol/ml-1/分钟时，肿瘤生长减少了83%。与活化CP对抗肿瘤疗效的显著影响相反，几乎未观察到药代动力学对4-OH-CP毒性的影响。因此，在调整药代动力学以产生恒定水平后，导致50%动物死亡的活化CP的生物利用度约为89μmol/ml-1/分钟，单次推注后约为79μmol/ml-1/分钟。所展示的实验表明，通过调整药代动力学，P1的治疗指数（定义为导致50%动物死亡的生物利用度与导致90%肿瘤生长抑制的生物利用度之比）可以增加一倍以上。
