Blaney S M, Balis F M, Hegedus L, Heideman R L, McCully C, Murphy R F, Kelley J A, Poplack D G
Walter Reed Army Medical Center, Washington, DC 20307.
Cancer Res. 1990 Dec 15;50(24):7915-9.
The plasma and cerebrospinal fluid pharmacokinetics of cyclopentenyl cytosine (CPE-C) were studied following i.v. bolus and continuous i.v. infusion in male rhesus monkeys. Following an i.v. bolus dose of 100 mg/m2 plasma elimination of CPE-C was biexponential with a mean t1/2 alpha of 8.4 min, a mean t1/2 beta of 36 min, and a total clearance (CLTB) of 662 ml/min/m2, which is 5- to 10-fold higher than clearance rates in rodents and dogs. Less than 20% of the total dose of CPE-C was excreted unchanged in the urine. The remainder was excreted as the inactive deamination product cyclopentenyl uridine (CPE-U). The ratio of the areas under the plasma concentration versus time curves of CPE-U to CPE-C was 7.0 +/- 2.4 following i.v. bolus CPE-C. The cerebrospinal fluid:plasma ratios of CPE-C and CPE-U were 0.08 and 0.30, respectively. Continuous i.v. infusion of CPE-C was compared to continuous infusion of 1-beta-D-arabinofuranosylcytosine in two monkeys. Steady state plasma concentrations, normalized to a dose of 12.5 mg/m2/h of CPE-C and an equimolar dose of 1-beta-D-arabinofuranosylcytosine, were 2.1 and 0.53 microM, respectively. The steady state concentrations of their corresponding uridine metabolites (CPE-U and 1-beta-D-arabinofuranosyluridine) were 8.2 and 15.5 microM. The rapid elimination of CPE-C by deamination in the primate resulted in a much higher CLTB and considerably lower total drug exposure than in rodents and dogs that clear CPE-C at a much lower rate by renal excretion. These significant interspecies differences in the disposition of CPE-C should be considered in the selection of a starting dose and schedule for human trials and suggest that a pharmacologically directed dose escalation scheme should be used in the planned phase I studies.
在雄性恒河猴中静脉推注和持续静脉输注环戊烯基胞嘧啶（CPE-C）后，研究了其血浆和脑脊液药代动力学。静脉推注剂量为100mg/m²后，CPE-C的血浆消除呈双指数，平均t1/2α为8.4分钟，平均t1/2β为36分钟，总清除率（CLTB）为662ml/min/m²，比啮齿动物和犬类的清除率高5至10倍。CPE-C总剂量中不到20%以原形经尿液排泄。其余部分作为无活性的脱氨基产物环戊烯基尿苷（CPE-U）排泄。静脉推注CPE-C后，CPE-U与CPE-C的血浆浓度-时间曲线下面积之比为7.0±2.4。CPE-C和CPE-U的脑脊液与血浆之比分别为0.08和0.30。在两只猴子中，将CPE-C的持续静脉输注与1-β-D-阿拉伯呋喃糖基胞嘧啶的持续输注进行了比较。以12.5mg/m²/h的CPE-C剂量和等摩尔剂量的1-β-D-阿拉伯呋喃糖基胞嘧啶进行归一化后的稳态血浆浓度分别为2.1和0.53μM。其相应尿苷代谢物（CPE-U和1-β-D-阿拉伯呋喃糖基尿苷）的稳态浓度分别为8.2和15.5μM。灵长类动物中CPE-C通过脱氨基快速消除，导致CLTB比啮齿动物和犬类高得多，总药物暴露量低得多，而啮齿动物和犬类通过肾排泄以低得多的速率清除CPE-C。在选择人体试验的起始剂量和方案时，应考虑CPE-C处置方面这些显著的种间差异，并表明在计划的I期研究中应使用药理学指导的剂量递增方案。
