Miller A A, Kurschel E, Osieka R, Schmidt C G
Innere Universitätsklinik (Tumorforschung), West German Tumor Center, University of Essen Medical School, F.R.G.
Eur J Cancer Clin Oncol. 1987 Sep;23(9):1283-7. doi: 10.1016/0277-5379(87)90109-x.
Since cancer may be regarded as a disease of differentiation and sodium butyrate induces differentiation of malignant cells in vitro, a study of the clinical pharmacology of sodium butyrate was undertaken. Nine patients with acute myeloid (n = 1), acute monocytic (n = 1), acute myelomonocytic (n = 6) and acute undifferentiated (n = 1) leukemia were treated. Their median age was 52 (range, 27-78) years. Six of the nine patients were pretreated with cytostatic agents. Sodium butyrate was administered i.v. at a dosage of 500 mg/kg/day as continuous infusion over 10 days. A sensitive and reproducible high-performance liquid chromatographic separation was developed after derivatization of sodium butyrate with 2,4'-dibromoacetophenone employing crown ether catalysis. Plasma concentrations and urinary excretion of sodium butyrate were monitored during the 10 days of continuous infusion and for 2 days thereafter. During infusion, plasma concentrations increased 6-fold over the endogenous butyrate level and reached 39-59 microM. The area under the curve of the exogenous butyrate was 384 +/- 50 microM X day (mean +/- S.D.). After the end of infusion, concentrations declined rapidly with a half-life of 6.1 +/- 1.4 min, and reached pretreatment values within 1 hr. The total clearance rate was 83 +/- 12 ml/kg/min and the volume of distribution 738 +/- 245 ml/kg. The excreted amounts of butyrate in the urine were minimal as compared to the infused dose. Although excretion by other organs was not ruled out, it is suggested that the infused sodium butyrate was rapidly metabolized. A significant increase in peripheral blast cells was observed, whereas bone marrow cytologies before and after treatment did not reveal a significant change in blasts. Differential counts of peripheral white blood cells did not show significant changes. No toxicity was encountered. The apparent lack of clinical efficacy may be explained by the low plasma levels of sodium butyrate due to its short half-life in vivo. In comparison, concentrations reported for in vitro studies were at least 10 times higher.
由于癌症可被视为一种分化疾病，且丁酸钠在体外可诱导恶性细胞分化，因此开展了一项丁酸钠临床药理学研究。对9例急性髓系白血病（n = 1）、急性单核细胞白血病（n = 1）、急性粒单核细胞白血病（n = 6）和急性未分化白血病（n = 1）患者进行了治疗。他们的中位年龄为52岁（范围27 - 78岁）。9例患者中有6例曾接受过细胞抑制剂预处理。丁酸钠以500 mg/kg/天的剂量静脉内持续输注10天。采用冠醚催化，丁酸钠与2,4'-二溴苯乙酮衍生化后，建立了一种灵敏且可重复的高效液相色谱分离方法。在持续输注的10天期间及之后2天监测丁酸钠的血浆浓度和尿排泄情况。输注期间，血浆浓度比内源性丁酸盐水平增加了6倍，达到39 - 59 μM。外源性丁酸盐的曲线下面积为384 ± 50 μM×天（均值±标准差）。输注结束后，浓度迅速下降，半衰期为6.1 ± 1.4分钟，并在1小时内恢复到预处理值。总清除率为83 ± 12 ml/kg/分钟，分布容积为738 ± 245 ml/kg。与输注剂量相比，尿中丁酸盐的排泄量极少。尽管不排除其他器官的排泄，但提示输注的丁酸钠迅速被代谢。观察到外周原始细胞显著增加，而治疗前后的骨髓细胞学检查未显示原始细胞有显著变化。外周白细胞分类计数未显示显著变化。未发现毒性。临床疗效明显缺乏可能是由于丁酸钠在体内半衰期短导致血浆水平低所致。相比之下，体外研究报道的浓度至少高10倍。
