Speyer J L, Sugarbaker P H, Collins J M, Dedrick R L, Klecker R W, Myers C E
Cancer Res. 1981 May;41(5):1916-22.
Intrahepatic tumor is a major problem in clinical oncology. While direct intravascular infusions provide high local drug concentrations and variable rates of tumor response, they are limited by technical considerations and complications. In this study, we have tested whether high portal venous and hepatic arterial concentrations of 5-fluorouracil (5-FUra) can be achieved by administering drug via peritoneal dialysis. Four patients with metastatic colon carcinoma had a Tenckhoff catheter surgically implanted. During dialysis therapy with 4 mM 5-FUra, simultaneous samples of peritoneal fluid and of portal venous, hepatic venous, and peripheral venous, and arterial blood were obtained, and 5-FUra concentrations were determined. Mean peak portal vein drug concentrations were 60 microM and exceeded the measured concentrations in the other vessels. Total drug exposures as measured by concentration x time (mM x min) during Exchange 1 were: portal, 3.8 +/- 0.65; hepatic vein, 0.97 +/- 0.44; peripheral vein, 0.90 +/- 0.32; and arterial, 1.1 +/- 0.26. During Exchange 7, total drug exposures were: portal, 6.3 +/- 1.4; hepatic vein, 2.5 +/- 1.3; peripheral vein, 2.3 +/- 1.1; and arterial, 2.7 +/- .85. The fraction of i.p. drug that exited the peritoneal cavity through the portal venous system ranged from 0.29 to 1.0. This variation resulted in part from uncertainty in estimating portal blood flow and gastrointestinal drug elimination. Calculated hepatic extraction was 67% (range, 0.23 to 0.89). Extrahepatic metabolism was demonstrated. Measured 5-FUra concentrations compared favorably to values predicted by a pharmacokinetic model for 5-FUra. Dialysis therapy (i.p.) with 5-FUra provides a means of achieving high drug concentrations for treating both i.p. and intrahepatic tumor. Further clinical testing of this route of administration is warranted.
肝内肿瘤是临床肿瘤学中的一个主要问题。虽然直接血管内输注可提供高局部药物浓度和不同的肿瘤反应率，但它们受到技术因素和并发症的限制。在本研究中，我们测试了通过腹膜透析给药是否能使门静脉和肝动脉中的5-氟尿嘧啶（5-FUra）达到高浓度。4例转移性结肠癌患者接受了Tenckhoff导管的手术植入。在用4 mM 5-FUra进行透析治疗期间，同时采集腹膜液、门静脉、肝静脉、外周静脉和动脉血的样本，并测定5-FUra浓度。门静脉药物平均峰值浓度为60 microM，超过了其他血管中测得的浓度。在第1次交换期间，以浓度×时间（mM×min）测量的总药物暴露量为：门静脉，3.8±0.65；肝静脉，0.97±0.44；外周静脉，0.90±0.32；动脉，1.1±0.26。在第7次交换期间，总药物暴露量为：门静脉，6.3±1.4；肝静脉，2.5±1.3；外周静脉，2.3±1.1；动脉，2.7±0.85。经门静脉系统离开腹膜腔的腹腔内药物分数范围为0.29至1.0。这种变化部分是由于估计门静脉血流和胃肠道药物消除存在不确定性。计算得出的肝脏提取率为67%（范围为0.23至0.89）。证实存在肝外代谢。测得的5-FUra浓度与5-FUra药代动力学模型预测的值相比具有优势。用5-FUra进行透析治疗（腹腔内）为治疗腹腔内和肝内肿瘤提供了一种实现高药物浓度的方法。这种给药途径值得进一步进行临床试验。
