Berg S L, Balis F M, McCully C L, Godwin K S, Poplack D G
Pediatric Branch, National Cancer Institute, Bethesda, MD 20892.
Cancer Res. 1991 Oct 15;51(20):5467-70.
Pyrazoloacridine is a rationally synthesized acridine derivative with in vitro activity against solid tumor cell lines, noncycling and hypoxic cells, and tumor cell lines that exhibit the multidrug resistance phenotype. The pharmacokinetic behavior of pyrazoloacridine after a 1- or 24-h i.v. infusion was studied in 5 rhesus monkeys that received a total of 10 courses of pyrazoloacridine at 300 or 600 mg/m2. Pyrazoloacridine levels in plasma and cerebrospinal fluid were measured by high-pressure liquid chromatography. For 1-h infusions, the plasma disappearance was biexponential with a t 1/2 alpha of 31 min and t 1/2 beta of 11 h. The mean volume of distribution at steady state was 1380 liters/m2. The clearance was 1660 ml/min/m2. For the 300 mg/m2 dose, the mean area under the concentration-time curve was 759 microM.min, and the mean peak concentration was 1.3 microM. For the 600 mg/m2 dose, the area under the concentration-time curve was 1330 microM.min, and the peak concentration was 2.5 microM. The steady-state plasma concentrations during the 24-h continuous infusions were 0.27 microM for the 300 mg/m2 dose and 0.45 microM for the 600 mg/m2 dose. The mean clearance calculated from these steady-state concentrations was 2420 ml/min/m2. Cerebrospinal fluid levels were less than 0.1 microM for all doses and schedules. There was no evidence of toxicity at any dose or schedule. These results contrast strikingly with those obtained in mice and dogs in which, despite a more rapid clearance of pyrazoloacridine, significant toxicities were observed at doses that were nontoxic in the monkey. These interspecies differences in the pharmacokinetic and pharmacodynamic behavior of pyrazoloacridine have important implications for the design of Phase I trials in humans.
吡唑并吖啶是一种合理合成的吖啶衍生物，具有体外抗实体瘤细胞系、非循环及缺氧细胞以及表现出多药耐药表型的肿瘤细胞系的活性。在5只恒河猴中研究了静脉输注1小时或24小时后吡唑并吖啶的药代动力学行为，这些恒河猴共接受了10个疗程的吡唑并吖啶，剂量为300或600mg/m²。通过高压液相色谱法测量血浆和脑脊液中的吡唑并吖啶水平。对于1小时输注，血浆消除呈双指数形式，t 1/2α为31分钟，t 1/2β为11小时。稳态分布容积平均为1380升/m²。清除率为1660毫升/分钟/m²。对于300mg/m²剂量，浓度-时间曲线下的平均面积为759微摩尔·分钟，平均峰值浓度为1.3微摩尔。对于600mg/m²剂量，浓度-时间曲线下的面积为1330微摩尔·分钟，峰值浓度为2.5微摩尔。24小时持续输注期间，300mg/m²剂量的稳态血浆浓度为0.27微摩尔，600mg/m²剂量为0.45微摩尔。根据这些稳态浓度计算的平均清除率为2420毫升/分钟/m²。所有剂量和给药方案的脑脊液水平均低于0.1微摩尔。在任何剂量或给药方案下均未发现毒性证据。这些结果与在小鼠和狗中获得的数据形成显著对比，在小鼠和狗中，尽管吡唑并吖啶清除更快，但在对猴子无毒的剂量下却观察到了明显的毒性。吡唑并吖啶在药代动力学和药效学行为上的这些种间差异对人类I期试验的设计具有重要意义。
