Thibault A, Cooper M R, Figg W D, Venzon D J, Sartor A O, Tompkins A C, Weinberger M S, Headlee D J, McCall N A, Samid D
Clinical Pharmacology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Cancer Res. 1994 Apr 1;54(7):1690-4.
Phenylacetate has recently been shown to suppress tumor growth and promote differentiation in experimental models. A phase I trial of phenylacetate was conducted in 17 patients with advanced solid tumors. Each patient received a single i.v. bolus dose followed by a 14-day continuous i.v. infusion of the drug. Twenty-one cycles of therapy were administered at four dose levels, achieved by increasing the rate of the continuous i.v. infusion. Phenylacetate displayed nonlinear pharmacokinetics [Km = 105.1 +/- 44.5 (SD) microgram/ml, Vmax = 24.1 +/- 5.2 mg/kg/h and Vd = 19.2 +/- 3.3 L]. There was also evidence for induction of drug clearance. Ninety-nine % of phenylacetate elimination was accounted for by conversion to phenylacetylglutamine, which was excreted in the urine. Continuous i.v. infusion rates resulting in serum phenylacetate concentrations exceeding Km often resulted in rapid drug accumulation and dose-limiting toxicity, which consisted of reversible central nervous system depression, preceded by emesis. Three of nine patients with metastatic, hormone-refractory prostate cancer maintained stable prostatic specific antigen levels for more than 2 months; another had less bone pain. One of six patients with glioblastoma multiforme, whose steroid dosage has remained unchanged for the duration of therapy, has sustained functional improvement for more than 9 months. The use of adaptive control with feedback for the dosing of each patient enabled us to safely maintain stable phenylacetate concentrations up to the range of 200-300 micrograms/ml, which resulted in clinical improvement in some patients with advanced disease.
最近的研究表明，苯乙酸在实验模型中具有抑制肿瘤生长和促进分化的作用。一项针对17例晚期实体瘤患者的苯乙酸I期试验展开。每位患者接受单次静脉推注剂量，随后进行为期14天的药物持续静脉输注。通过提高持续静脉输注速率，在四个剂量水平上进行了21个疗程的治疗。苯乙酸呈现非线性药代动力学[米氏常数（Km）=105.1±44.5（标准差）微克/毫升，最大反应速率（Vmax）=24.1±5.2毫克/千克/小时，分布容积（Vd）=19.2±3.3升]。同时也有证据表明存在药物清除诱导现象。99%的苯乙酸通过转化为苯乙酰谷氨酰胺而被清除，后者经尿液排出。持续静脉输注速率导致血清苯乙酸浓度超过Km时，常常会导致药物快速蓄积和剂量限制性毒性，表现为可逆性中枢神经系统抑制，之前伴有呕吐。9例转移性、激素难治性前列腺癌患者中有3例前列腺特异性抗原水平稳定超过2个月；另1例骨痛减轻。6例多形性胶质母细胞瘤患者中有1例，在治疗期间类固醇剂量保持不变，功能持续改善超过9个月。对每位患者采用反馈式自适应控制给药，使我们能够安全地将苯乙酸浓度稳定维持在200 - 300微克/毫升范围内，这使得一些晚期疾病患者的临床症状得到改善。
