Thompson Patrick A, Berg Stacey L, Aleksic Alexander, Kerr Jody Z, McGuffey Leticia, Dauser Robert, Nuchtern Jed G, Hausheer Fred, Blaney Susan M
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Cancer Chemother Pharmacol. 2004 Jun;53(6):527-32. doi: 10.1007/s00280-004-0765-6. Epub 2004 Mar 2.
BNP1350 (7-[(2-trimethylsilyl)ethyl]-20(S)-camptothecin, karenitecin), a highly lipophilic camptothecin, a high percentage of which is maintained in the active lactone form under physiologic conditions, has recently entered clinical trials in adults and children. BNP1350 has shown significant preclinical antitumor activity against a wide variety of adult and pediatric tumor cell lines. This study was undertaken to define the pharmacokinetics of BNP1350 in both plasma and cerebrospinal fluid (CSF) in a nonhuman primate model.
Four nonhuman primates with indwelling Ommaya reservoirs received BNP1350, 0.1 mg/kg i.v, administered as a 60-min infusion. Frequent plasma and CSF samples were obtained for quantitation of BNP1350 concentrations using reverse-phase high-pressure liquid chromatography (HPLC).
Disappearance of the lactone form from the plasma was biexponential with a mean distribution half-life of 57.5 min (CV +/-33%) and an elimination half-life of 457 min (CV +/-24%). The volume of distribution for the central compartment was 1.36 l/kg (CV +/-27%) and clearance from the central compartment was 10.6 ml/kg per minute (CV +/-28%). The peripheral compartment volume of distribution was 1.96 l/kg (CV +/-8.4%). Peak CSF lactone concentration, which occurred at 12 to 25 min after the end of the infusion, was 0.33 n M (CV +/-71%).
The ratio of the CSF AUC to the plasma AUC was less than 5% (range 0.4% to 3.0%), similar to other highly protein-bound topoisomerase inhibitors such as 9-aminocamptothecin and SN-38 (the active metabolite of irinotecan).
BNP1350（7-[(2-三甲基硅烷基)乙基]-20(S)-喜树碱，卡瑞立辛）是一种高度亲脂性的喜树碱，在生理条件下其很大一部分以活性内酯形式存在，最近已进入成人和儿童的临床试验。BNP1350已显示出对多种成人和儿童肿瘤细胞系具有显著的临床前抗肿瘤活性。本研究旨在确定非人类灵长类动物模型中BNP1350在血浆和脑脊液（CSF）中的药代动力学。
四只植入奥马亚储液器的非人类灵长类动物接受静脉注射BNP1350，剂量为0.1mg/kg，输注时间为60分钟。使用反相高压液相色谱（HPLC）频繁采集血浆和脑脊液样本，以定量BNP1350浓度。
血浆中内酯形式的消失呈双指数形式，平均分布半衰期为57.5分钟（CV±33%），消除半衰期为457分钟（CV±24%）。中央室的分布容积为1.36l/kg（CV±27%），中央室的清除率为每分钟10.6ml/kg（CV±28%）。外周室的分布容积为1.96l/kg（CV±8.4%）。输注结束后12至25分钟出现脑脊液内酯浓度峰值，为0.33nM（CV±71%）。
脑脊液AUC与血浆AUC之比小于5%（范围为0.4%至3.0%），与其他高蛋白结合的拓扑异构酶抑制剂如9-氨基喜树碱和SN-38（伊立替康的活性代谢物）相似。
