Fung L K, Ewend M G, Sills A, Sipos E P, Thompson R, Watts M, Colvin O M, Brem H, Saltzman W M
School of Chemical Engineering, Cornell University, Ithaca, New York 14853, USA.
Cancer Res. 1998 Feb 15;58(4):672-84.
Polymeric interstitial chemotherapy increases survival of humans with recurrent gliomas and animals with transplanted tumors in the brain, but the relationship between rates of drug release from polymer implants and drug concentration in brain tissue is unknown. This work presents a pharmacokinetic framework for application of this new modality of chemotherapy delivery in primates. Either [3H]carmustine, 4-hydroperoxycyclophosphamide (4-HC), or paclitaxel was encapsulated in a polyanhydride pellet (28-41 microCi/animal, 40 mg/animal), which was implanted intracranially in cynomolgus monkeys (Macaca fascicularis); (n = 17) for up to 30 days. Drug concentrations in the brain, blood, and cerebrospinal fluid were measured by quantitative autoradiography, TLC, and scintillation counting. High drug concentrations (0.5-3.5 mM for carmustine, 0.3-0.4 mM for 4-HC, and 0.2-1.0 mM for paclitaxel) were measured within the first 3 mm from the polymer implant; significant (0.4 microM for carmustine, 3 microM for 4-HC, and 0.6 microM for paclitaxel) concentrations were measured up to approximately 5 cm from the implant as long as 30 days after implantation. Pharmacokinetic analysis indicated that tissue exposure to carmustine area under concentration-time curve achieved by polymeric delivery was 4-1200 times higher than that produced by i.v. administration of a higher dose.
聚合物间质化疗可提高复发性神经胶质瘤患者及脑内移植瘤动物的生存率，但聚合物植入物的药物释放速率与脑组织中药物浓度之间的关系尚不清楚。这项工作提出了一个药代动力学框架，用于在灵长类动物中应用这种新的化疗给药方式。将[3H]卡莫司汀、4-氢过氧环磷酰胺（4-HC）或紫杉醇封装在聚酸酐微丸中（每只动物28-41微居里，40毫克），然后将其颅内植入食蟹猴（猕猴）体内（n = 17），最长植入30天。通过定量放射自显影、薄层色谱法和闪烁计数法测量脑、血液和脑脊液中的药物浓度。在距聚合物植入物3毫米范围内测得高药物浓度（卡莫司汀为0.5-3.5毫摩尔/升，4-HC为0.3-0.4毫摩尔/升，紫杉醇为0.2-1.0毫摩尔/升）；在植入后长达30天的时间里，在距植入物约5厘米处测得显著浓度（卡莫司汀为0.4微摩尔/升，4-HC为3微摩尔/升，紫杉醇为0.6微摩尔/升）。药代动力学分析表明，聚合物给药方式使组织暴露于卡莫司汀的浓度-时间曲线下面积比静脉注射更高剂量时高4至
