Piscitelli S C, Thibault A, Figg W D, Tompkins A, Headlee D, Lieberman R, Samid D, Myers C E
Pharmacy Department, National Institutes of Health, Bethesda, Maryland, USA.
J Clin Pharmacol. 1995 Apr;35(4):368-73. doi: 10.1002/j.1552-4604.1995.tb04075.x.
Phenylacetate, an inducer of tumor cytostasis and differentiation, shows promise as a relatively nontoxic antineoplastic agent. Phenylacetate, however, has an unpleasant odor that might limit patient acceptability. Phenylbutyrate, an odorless compound that also has activity in tumor models, is known to undergo rapid conversion to phenylacetate by beta-oxidation in vivo. This phase I study examined the pharmacokinetics of phenylbutyrate and characterized the disposition of the two metabolites, phenylacetate and phenylacetylglutamine. Fourteen patients with cancer (aged 51.8 +/- 13.8 years) received a 30-minute infusion of phenylbutyrate at 3 dose levels (600, 1200, and 2000 mg/m2). Serial blood samples and 24-hour urine collections were obtained. Samples were assayed by high-performance liquid chromatography. A model to simultaneously describe the pharmacokinetics of all three compounds was developed using ADAPT II. Data were modeled as molar equivalents. The model fit the data well as shown by mean (+/- SD) coefficients of determination (r2) for phenylbutyrate, phenylacetate, and phenylacetylglutamine, which were 0.96 +/- 0.07, 0.88 +/- 0.10, and 0.92 +/- 0.06, respectively. The intrapatient coefficient of variation percentage (CV%) around the parameter estimates were small (range 7.2-33.5%). Phenylbutyrate achieved peak concentrations in the range of in vitro tumor activity (500-2000 mumol/L) and exhibited saturable elimination (Km = 34.1 +/- 18.1 micrograms/mL and Vmax = 18.1 +/- 18 mg/h/kg). Metabolism was rapid; the times to maximum concentration for phenylacetate and phenylacetylglutamine were 1 and 2 hours, respectively. The conversion of phenylbutyrate to phenylacetate was extensive (80 +/- 12.6%), but serum concentrations of phenylacetate were low owing to rapid, subsequent conversion to phenylacetylglutamine.(ABSTRACT TRUNCATED AT 250 WORDS)
苯乙酸是一种肿瘤细胞生长抑制和分化诱导剂，作为一种相对无毒的抗肿瘤药物显示出前景。然而，苯乙酸有难闻的气味，这可能会限制患者的接受度。苯丁酸盐是一种无味的化合物，在肿瘤模型中也有活性，已知它在体内通过β-氧化迅速转化为苯乙酸。这项I期研究检测了苯丁酸盐的药代动力学，并对两种代谢产物苯乙酸和苯乙酰谷氨酰胺的处置情况进行了表征。14名癌症患者（年龄51.8±13.8岁）接受了30分钟的苯丁酸盐静脉输注，剂量为3个水平（600、1200和2000mg/m2）。采集了系列血样和24小时尿液。样本通过高效液相色谱法进行分析。使用ADAPT II开发了一个同时描述所有三种化合物药代动力学的模型。数据以摩尔当量进行建模。该模型对数据拟合良好，苯丁酸盐、苯乙酸和苯乙酰谷氨酰胺的平均（±标准差）决定系数（r2）分别为0.96±0.07、0.88±0.10和0.92±0.06。参数估计值周围的患者内变异系数百分比（CV%）较小（范围为7.2 - 33.5%）。苯丁酸盐达到了体外肿瘤活性范围内的峰值浓度（500 - 2000μmol/L），并表现出饱和消除（Km = 34.1±18.1μg/mL，Vmax = 18.1±18mg/h/kg）。代谢迅速；苯乙酸和苯乙酰谷氨酰胺达到最大浓度的时间分别为1小时和2小时。苯丁酸盐向苯乙酸的转化广泛（80±12.6%），但由于随后迅速转化为苯乙酰谷氨酰胺，苯乙酸的血清浓度较低。（摘要截断于250字）
