Kilburn Lindsay B, Bonate Peter L, Blaney Susan M, McGuffey Leticia, Nuchtern Jed G, Dauser Robert, Thompson Patrick, Gibson Brian W, Berg Stacey L
Texas Children's Cancer Center, Baylor College of Medicine, 6621 Fannin St., MC:3-3320, Houston, TX 77030, USA.
Cancer Chemother Pharmacol. 2009 Jul;64(2):335-40. doi: 10.1007/s00280-008-0875-7. Epub 2008 Nov 29.
To evaluate the plasma and cerebrospinal fluid (CSF) pharmacokinetics and CSF penetration of tasidotin and metabolites in a nonhuman primate model.
Tasidotin 0.75 mg/kg was administered intravenously. The plasma and CSF concentrations of tasidotin and its metabolites were determined. Pharmacokinetic parameters were estimated using model-independent and model-dependent methods.
The mean (+/-SD) CSF:plasma AUC ratio for tasidotin was 1.1 +/- 0.4. For tasidotin, tasidotin-C-carboxylate and desprolyl-tasidotin-C-carboxylate the plasma AUCs (mean +/- SD) were 30 +/- 10, 54 +/- 19 and 12 +/- 2 microM min, and apparent plasma half-lives were 27 +/- 4, 229 +/- 73 and 100 +/- 29 min. The plasma clearance of tasidotin was 44 +/- 14 ml/min/kg. The CSF AUC and half-life of tasidotin was 28 +/- 10 microM min and 96 +/- 40 min. The model-dependent plasma clearance was 35 ml/min/kg for tasidotin and 2 ml/min/kg for tasidotin-C-carboxylate.
Tasidotin penetrates into the CSF well and further evaluation of its activity in the treatment of central nervous system malignancies should be considered.
在非人类灵长类动物模型中评估他西多汀及其代谢产物的血浆和脑脊液药代动力学以及脑脊液穿透情况。
静脉注射0.75mg/kg他西多汀。测定他西多汀及其代谢产物的血浆和脑脊液浓度。使用非模型依赖和模型依赖方法估算药代动力学参数。
他西多汀的平均（±标准差）脑脊液：血浆AUC比值为1.1±0.4。对于他西多汀、他西多汀-C-羧酸盐和去脯氨酰-他西多汀-C-羧酸盐，血浆AUC（平均±标准差）分别为30±10、54±19和12±2μM·min，表观血浆半衰期分别为27±4、229±73和100±29min。他西多汀的血浆清除率为44±14ml/min/kg。他西多汀的脑脊液AUC和半衰期分别为28±10μM·min和96±40min。模型依赖的血浆清除率对于他西多汀为35ml/min/kg，对于他西多汀-C-羧酸盐为2ml/min/kg。
他西多汀能很好地穿透进入脑脊液，应考虑进一步评估其在治疗中枢神经系统恶性肿瘤中的活性。
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