Blaney S M, Takimoto C, Murry D J, Kuttesch N, McCully C, Cole D E, Godwin K, Balis F M
Texas Children's Cancer Center, Houston 77030, USA.
Cancer Chemother Pharmacol. 1998;41(6):464-8. doi: 10.1007/s002800050768.
The plasma and cerebrospinal fluid (CSF) pharmacokinetics of the camptothecin analogs, 9-aminocamptothecin (9-AC) and irinotecan, were studied in a nonhuman primate model to determine their CSF penetration.
9-AC, 0.2 mg/kg (4 mg/m2) or 0.5 mg/kg (10 mg/m2), was infused intravenously over 15 min and irinotecan, 4.8 mg/kg (96 mg/m2) or 11.6 mg/kg (225 mg/m2), was infused over 30 min. Plasma and CSF samples were obtained at frequent intervals over 24 h. Lactone and total drug forms of 9-AC, irinotecan, and the active metabolite of irinotecan, SN-38, were quantified by reverse-phase HPLC.
9-AC lactone had a clearance (CL) of 2.1 +/- 0.9 l/kg per h, a volume of distribution at steady state (Vd[ss]) of 1.6 +/- 0.7 l/kg and a half-life (t1/2) of 3.2 +/- 0.8 h. The lactone form of 9-AC accounted for 26 +/- 7% of the total drug in plasma. The CSF penetration of 9-AC lactone was limited. CSF 9-AC lactone concentration peaked 30 to 45 min after the dose at 11 to 21 nM (0.5 mg/kg dose), and the ratio of the areas under the CSF and plasma concentration-time curves (AUC(CSF):AUC[P]) was only 3.5 +/- 2.1%. For irinotecan, the CL was 3.4 +/- 0.4 l/kg per h, the Vd(ss) was 7.1 +/- 1.3 l/kg, and the t1/2 was 4.9 +/- 2.2 h. Plasma AUCs of the lactone form of SN-38 were only 2.0% to 2.4% of the AUCs of irinotecan lactone. The lactone form of irinotecan accounted for 26 +/- 5% of the total drug in plasma, and the lactone form of SN-38 accounted for 55 +/- 6% of the total SN-38 in plasma. The AUC(CSF):AUC(P) ratio for irinotecan lactone was 14 +/- 3%. SN-38 lactone and carboxylate could not be measured (< 1.0 nM) in CSF. The AUC(CSF):AUC(P) ratio for SN-38 lactone was estimated to be < or = 8%.
Despite their structural similarity, the CSF penetration of 9-AC and SN-38 is substantially less than that of topotecan which we previously found to have an AUC(CSF):AUC(P) ratio of 32%.
在非人类灵长类动物模型中研究喜树碱类似物9-氨基喜树碱（9-AC）和伊立替康的血浆和脑脊液（CSF）药代动力学，以确定它们的脑脊液穿透情况。
9-AC，0.2mg/kg（4mg/m²）或0.5mg/kg（10mg/m²），在15分钟内静脉输注，伊立替康，4.8mg/kg（96mg/m²）或11.6mg/kg（225mg/m²），在30分钟内输注。在24小时内频繁采集血浆和脑脊液样本。通过反相高效液相色谱法定量9-AC、伊立替康及其活性代谢物SN-38的内酯和总药物形式。
9-AC内酯的清除率（CL）为2.1±0.9l/kg每小时，稳态分布容积（Vd[ss]）为1.6±0.7l/kg，半衰期（t1/2）为3.2±0.8小时。9-AC内酯形式占血浆中总药物的26±7%。9-AC内酯的脑脊液穿透有限。脑脊液中9-AC内酯浓度在给药后30至45分钟达到峰值，为11至21nM（0.5mg/kg剂量），脑脊液和血浆浓度-时间曲线下面积之比（AUC(CSF):AUC[P]）仅为3.5±2.1%。对于伊立替康，CL为3.4±0.4l/kg每小时，Vd(ss)为7.1±1.3l/kg，t1/2为4.9±2.2小时。SN-38内酯形式的血浆AUC仅为伊立替康内酯AUC的2.0%至2.4%。伊立替康内酯形式占血浆中总药物的26±5%，SN-38内酯形式占血浆中总SN-38的55±6%。伊立替康内酯的AUC(CSF):AUC(P)比值为14±3%。脑脊液中无法检测到SN-38内酯和羧酸盐（<1.0nM）。SN-38内酯的AUC(CSF):AUC(P)比值估计≤8%。
尽管9-AC和SN-38结构相似，但它们的脑脊液穿透性明显低于我们之前发现的拓扑替康，拓扑替康的AUC(CSF):AUC(P)比值为32%。
