DISPOSITION OF PHENYLBUTYRATE AND ITS METABOLITES, PHENYLACETATE AND PHENYLACETYLGLUTAMINE
DISPOSITION OF PHENYLBUTYRATE AND ITS METABOLITES, PHENYLACETATE AND PHENYLACETYLGLUTAMINE
复制标题
DOI：
10.1002/j.1552-4604.1995.tb04075.x
复制
发表时间：
1995-04-01
影响因子：
2.9
通讯作者：
MYERS, CE
中科院分区：
文献类型：
--
作者：
PISCITELLI, SC;THIBAULT, A;MYERS, CE
苯乙酸酯是一种肿瘤细胞停滞和分化的诱导剂，作为一种相对无毒的抗肿瘤药物很有希望，但苯乙酸酯有一种令人不快的气味，可能会限制患者的接受度。苯丁酸酯是一种无味化合物，在肿瘤模型中也有活性，已知在体内通过β-氧化快速转化为苯乙酸酯。本研究I期研究了苯丁酸苯酯的药代动力学，并研究了苯乙酸苯乙酯和苯乙酰谷氨酰胺两种代谢物在体内的分布。14例癌症患者(年龄51.8+/-13.8岁)按600、1200和2000 mg/m(2)3个剂量水平输注30分钟，采集连续血样和24小时尿液标本。样品用高效液相色谱检测。使用Adapt II开发了一个同时描述所有三种化合物的药代动力学的模型。数据被模拟为摩尔等价物。苯丁酸酯、苯乙酸乙酯和苯乙酰谷氨酰胺的平均(+/-SD)测定系数(r(2))分别为0.96+/-0.07、0.88+/-0.10和0.92+/-0.06。参数估计周围的患者内变异系数百分比(CV%)很小(范围7.2-33.5%)。丁酸苯酯在体外肿瘤活性(5 0 0~2 0 0 0 m ol/L)范围内达到峰值浓度，并呈现饱和消除(K-m=34.1+/-18 m u g/m L，V-max=18.1+/-18 m g/h/kg)。代谢速度快，苯乙酸乙酯和苯乙酰谷氨酰胺的最大浓度分别为1和2小时。苯丁酸盐转化为苯乙酸乙酯的比例很高(80+/-12.6%)，但苯乙酸乙酯的血清浓度很低，这是因为苯乙酸乙酯随后迅速转化为苯乙酰谷氨酰胺。丁酸苯酯与乙酸苯酯的AUC之比为2.66。因此，苯丁酸酯可能不是苯乙酸乙酯的前体药物，应作为一种独立的抗肿瘤药物进行研究。
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/m(2)), 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 Ft the data well os shown by mean (+/-SD) coefficients of determination (r(2)) 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 mu mol/L) and exhibited saturable elimination (K-m = 34.1 +/- 18.1 mu g/mL and V-max = 18.1 +/- 18 mg/h/kg). Metabolism was rapid; the rimes 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. The ratio of phenylbutyrate AUC to phenylacetate AUC was 2.66. Thus, phenylbutyrate may not be a prodrug for phenylacetate and should be pursued as an independent antitumor agent.