Walton M I, Gibson W, Aherne G W, Lawrence N, Stephens T C, Smith M N, Jackman A L
CRC Centre for Cancer Therapeutics, Sutton, Surrey, UK.
J Pharmacol Exp Ther. 1996 May;277(2):909-16.
CB30900 is a novel, potent thymidylate synthase inhibitor which can not be polyglutamated and may be active in cancers expressing low or defective folylpolyglutamate synthetase. Pharmacokinetics were studied in mouse tumors and tissues after bolus or infusion protocols. Elimination was triphasic after 100 mg kg-1 i.v. (T 1/2 alpha, 2.8 min; T 1/2 beta, 19.1 min and T 1/2 gamma, 4.1 hr). Peak concentrations were 716 microM; clearance, 1.19 ml g-1 hr-1; and area under the curve (AUC 0-2 hr), 131 microM hr. Biphasic elimination occurred after i.p. administration and was comparable to the i.v. route giving complete i.p. bioavailability. Kidney concentrations were similar to plasma (AUC 0-2 hr, 84.3 microM hr). CB30900 concentrations in the gut increased steadily with time (AUC 0-2 hr, 645 microM hr) and liver drug concentrations were 7-fold greater than plasma (AUC 0-2 hr, 847 microM hr). Peak tumor concentrations occurred at 30 min and were 27% of plasma concentrations, but tumor drug clearance was markedly slower than for plasma (T 1/2, 51 +/- 8.2 min, mean +/- S.E.). CB30900 was remarkably stable in vivo with 93% of an administered dose recovered unchanged after 48 hr. Plasma drug binding was concentration-dependent, ranging from 93.3 to 76% over 1 to 500 microM. During 24 hr infusion (50 mg kg-1 s.c.), steady-state plasma concentrations were 3 microM, giving an AUC 0-24 hr of 71 microM hr. Kidney drug levels were similar to plasma but liver concentrations were elevated 7-fold. By contrast, tumor drug concentrations were about 0.5 microM (AUC 0-24 hr, 14.6 microM hr). However, these low plasma drug concentrations are growth inhibitory in vitro (24-hr exposure).
CB30900是一种新型强效胸苷酸合成酶抑制剂，它不能被聚谷氨酸化，可能对表达低水平或有缺陷的叶酰聚谷氨酸合成酶的癌症具有活性。在推注或输注给药方案后，对小鼠肿瘤和组织中的药代动力学进行了研究。静脉注射100mg/kg后，消除呈三相（半衰期α为2.8分钟；半衰期β为19.1分钟；半衰期γ为4.1小时）。峰值浓度为716微摩尔/升；清除率为1.19毫升/克/小时；曲线下面积（AUC 0 - 2小时）为131微摩尔·小时。腹腔注射后出现双相消除，与静脉注射途径相当，腹腔给药生物利用度完全。肾脏浓度与血浆相似（AUC 0 - 2小时，84.3微摩尔·小时）。肠道中CB30900的浓度随时间稳步增加（AUC 0 - 2小时，645微摩尔·小时），肝脏药物浓度比血浆高7倍（AUC 0 - 2小时，847微摩尔·小时）。肿瘤峰值浓度出现在30分钟时，为血浆浓度的27%，但肿瘤药物清除明显慢于血浆（半衰期，51±8.2分钟，平均值±标准误）。CB30900在体内非常稳定，48小时后93%的给药剂量未发生变化地被回收。血浆药物结合呈浓度依赖性，在1至500微摩尔范围内从93.3%至76%不等。在24小时皮下输注（50mg/kg）期间，稳态血浆浓度为3微摩尔，AUC 0 - 24小时为71微摩尔·小时。肾脏药物水平与血浆相似，但肝脏浓度升高7倍。相比之下，肿瘤药物浓度约为0.5微摩尔（AUC 0 - 24小时，14.6微摩尔·小时）。然而，这些低血浆药物浓度在体外具有生长抑制作用（24小时暴露）。
