Widemann B C, Balis F M, Godwin K S, McCully C, Adamson P C
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1928, USA.
Cancer Chemother Pharmacol. 1999;44(6):439-43. doi: 10.1007/s002800051116.
Raltitrexed (Tomudex), ZD1694) is a novel quinazoline folate analog that selectively inhibits thymidylate synthase. Intracellularly, raltitrexed is polyglutamated to its active form which can be retained in cells for prolonged periods. The pharmacokinetics of raltitrexed in plasma and cerebrospinal fluid (CSF) were studied in a nonhuman primate model.
Animals received 3 mg/m(2) (n = 1), 6 mg/m(2) (n = 3), or 10 mg/m(2) (n = 3) i.v. over 15 min, and frequent plasma samples were obtained over 48 h. CSF samples were drawn from an indwelling 4th ventricular Ommaya reservoir over 48 h. Plasma and CSF raltitrexed concentrations were measured with a novel, sensitive enzyme inhibition assay with a lower limit of quantification of 0.005 microM. A three-compartment pharmacokinetic model was fitted to the raltitrexed plasma concentration-time data.
The plasma concentration-time profile of raltitrexed was triexponential with a rapid initial decline and a prolonged terminal elimination phase (t(1/2) > 24 h), which was related to retention of raltitrexed in a deep tissue compartment. At the peak approximately 30% of the administered dose was in the deep tissue compartment, and 24 h after the dosing >20% of the administered dose remained in the body with >99% in the deep tissue compartment. The mean peak (end of infusion) plasma concentrations after the 3, 6, and 10 mg/m(2) doses were 1.5, 2.4 and 4.8 microM, respectively. The clearance of raltitrexed ranged from 110 to 165 ml/min per m(2), and the steady-state volume of distribution exceeded 200 l/m(2). The CSF penetration of raltitrexed was limited (0.6 to 2.0%) and drug could only be detected in the CSF following a 10 mg/m(2 )dose.
The elimination of raltitrexed is triexponential with a prolonged terminal elimination phase. The pharmacokinetic profile is consistent with extensive polyglutamation and intracellular retention of ralitrexed. The three-compartment model presented here may be useful for the analysis of the pharmacokinetics of raltitrexed in humans.
雷替曲塞（商品名：拓优得，ZD1694）是一种新型喹唑啉叶酸类似物，可选择性抑制胸苷酸合成酶。在细胞内，雷替曲塞会聚谷氨酸化成为其活性形式，并可在细胞内长时间留存。我们在非人类灵长类动物模型中研究了雷替曲塞在血浆和脑脊液（CSF）中的药代动力学。
动物静脉注射3mg/m²（n = 1）、6mg/m²（n = 3）或10mg/m²（n = 3），注射时间为15分钟，在48小时内频繁采集血浆样本。在48小时内从留置的第四脑室奥马亚贮液器采集脑脊液样本。采用一种新型的、灵敏的酶抑制测定法测量血浆和脑脊液中雷替曲塞的浓度，定量下限为0.005微摩尔。用三室药代动力学模型拟合雷替曲塞血浆浓度 - 时间数据。
雷替曲塞的血浆浓度 - 时间曲线呈三指数型，初始快速下降，终末消除期延长（t1/2 > 24小时），这与雷替曲塞在深部组织隔室中的留存有关。在峰值时，约30%的给药剂量存在于深部组织隔室中，给药后24小时，>20%的给药剂量仍留在体内，其中>99%在深部组织隔室中。3mg/m²、6mg/m²和10mg/m²剂量后的平均峰值（输注结束时）血浆浓度分别为1.5、2.4和4.8微摩尔。雷替曲塞的清除率为110至165毫升/分钟·m²，稳态分布容积超过200升/m²。雷替曲塞在脑脊液中的渗透有限（0.6%至2.0%），仅在10mg/m²剂量后能在脑脊液中检测到药物。
雷替曲塞的消除呈三指数型，终末消除期延长。药代动力学特征与雷替曲塞广泛的聚谷氨酸化和细胞内留存一致。本文提出的三室模型可能有助于分析雷替曲塞在人体内的药代动力学。
