Oldfield E H, Clark W C, Dedrick R L, Egorin M J, Austin H A, DeVroom H D, Joyce K M, Doppman J L
Cancer Res. 1987 Apr 1;47(7):1962-7.
During cancer chemotherapy toxicity to normal tissues often limits the tolerable dose. To increase drug delivery to tumor while maintaining tolerable systemic exposure, regional treatments, such as intraarterial drug delivery, have been used. Despite intraarterial delivery, systemic toxicity often remains the dose-limiting sensitivity. If systemic drug exposure could be reduced after intraarterial infusion, the intraarterial dose could be increased, which should increase the therapeutic response. We compared the pharmacokinetic advantage after cisplatin infusion into the internal carotid artery to that obtained after infusing cisplatin into the internal carotid artery during extracorporeal removal of cisplatin from the jugular blood by hemodialysis. Four patients with malignant gliomas received intracarotid cisplatin, 100 mg/m2 over 60 min, every 4 weeks. During one treatment, while cisplatin was infused into the internal carotid artery, the jugular blood was dialyzed extracorporeally at 300 ml/min and returned to the inferior vena cava. Seventy to 96% of the free platinum that entered the dialyzer was removed. By aspirating blood from the jugular vein at 300 ml/min, 30-79% of the ipsilateral carotid blood was collected for extracorporeal circulation. Hemodialysis of the cerebral venous drainage during intracarotid infusion reduced the systemic exposure to cisplatin by 51-61% when compared to the exposure from internal carotid artery infusion without hemodialysis. The pharmacokinetic advantage (brain/body exposure ratio) was increased from 3 to 5/1 during internal carotid artery infusion alone to as much as 15/1 during treatment combining intracarotid infusion with hemodialysis of the jugular blood. Systemic toxicity now limits the dose of cisplatin that can be administered safely. Increased tumor exposure without increased systemic toxicity may be possible with the technique described and greater doses of cisplatin. Assuming no associated local toxicities, the results of the current study indicate that the dose of intracarotid cisplatin can be increased while maintaining tolerable systemic exposure.
在癌症化疗期间，对正常组织的毒性常常限制了可耐受剂量。为了在维持可耐受的全身暴露的同时增加药物向肿瘤的递送，人们采用了区域治疗方法，如动脉内给药。尽管采用了动脉内给药，但全身毒性往往仍是剂量限制敏感性因素。如果在动脉内输注后能降低全身药物暴露，那么动脉内剂量就可以增加，这有望提高治疗反应。我们比较了顺铂注入颈内动脉后的药代动力学优势与在通过血液透析从颈静脉血中体外清除顺铂的过程中向颈内动脉注入顺铂后的药代动力学优势。4例恶性胶质瘤患者接受颈内动脉顺铂给药，剂量为100mg/m²，持续60分钟，每4周给药一次。在一次治疗中，当顺铂注入颈内动脉时，颈静脉血以300ml/分钟的速度进行体外透析，然后回流入下腔静脉。进入透析器的游离铂中有70%至96%被清除。以300ml/分钟的速度从颈静脉抽血时，同侧颈动脉血的30%至79%被采集用于体外循环。与未进行血液透析的颈内动脉输注相比，颈内动脉输注期间对脑静脉引流进行血液透析可使顺铂的全身暴露降低51%至61%。药代动力学优势（脑/体暴露比）从单纯颈内动脉输注时的3增至5/1，在颈内动脉输注联合颈静脉血液透析的治疗过程中增至高达15/1。目前全身毒性限制了能够安全给药的顺铂剂量。采用所述技术并使用更大剂量的顺铂，有可能在不增加全身毒性的情况下增加肿瘤暴露。假设无相关局部毒性，当前研究结果表明，在维持可耐受的全身暴露的同时，可以增加颈内动脉顺铂的剂量。
