非人类灵长类动物模型中 O4-苄基叶酸（O4BF）及其代谢物的血浆和中枢神经系统药代动力学。

Plasma and CNS pharmacokinetics of O4-benzylfolic acid (O4BF) and metabolite in a non-human primate model.

机构信息

Pediatric Oncology Branch, National Cancer Institute, 10 Center Drive, Building 10/Rm 1W-5750, Bethesda, MD 20892, USA.

出版信息

Cancer Chemother Pharmacol. 2011 Jun;67(6):1291-7. doi: 10.1007/s00280-010-1407-9. Epub 2010 Aug 20.

DOI:10.1007/s00280-010-1407-9

PMID:20725726

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6675565/

Abstract

PURPOSE

O(6)-alkylguanine-DNA alkyltransferase (AGT) repairs DNA damage from alkylating agents by transferring the alkyl adducts from the O(6)-position of guanine in DNA to AGT. The folate analog O(4)-benzylfolic acid (O(4)BF) is an inhibitor of AGT with reported selectivity of the alpha-folate receptor in tumors. We studied plasma and cerebrospinal fluid (CSF) pharmacokinetics and CSF penetration of O(4)BF in a non-human primate model.

METHODS

Rhesus monkeys (Macaca mulatta) received O(4)BF (10-50 mg/kg) intravenously, and serial blood and CSF samples were obtained. Analyte concentrations in plasma were measured by HPLC/photo diode array, and an HPLC/MS/MS assay was used for CSF samples.

RESULTS

A putative metabolite of O(4)BF was detected in plasma and CSF. O(4)BF and the metabolite inactivated purified AGT with ED(50) of 0.04 mcM. The median clearance of O(4)BF was 8 ml/min/kg and half-life was 1.1 h. The metabolite had a substantially longer half-life (>20 h) and greater AUC than O(4)BF. The AUC of the metabolite increased disproportionately to the dose of O(4)BF, suggesting saturable elimination. CSF penetration of O(4)BF and its metabolite was < 1%. At the 50 mg/kg dose level, the C(max) in CSF for O(4)BF was less than 0.09 mcM and for the metabolite the C(max) ranged from 0.02 to 0.04 mcM (O(4)BF equivalents).

CONCLUSIONS

Concentrations of O(4)BF and the metabolite in CSF exceeded the ED(50) of AGT; however, recently reported lack of receptor specificity and pharmacokinetic data suggesting saturable elimination of both O(4)BF and its metabolite may limit dose-escalation and future clinical development of this agent.

摘要

目的

O(6)-烷基鸟嘌呤-DNA 烷基转移酶（AGT）通过将 DNA 中鸟嘌呤的 O(6)-位上的烷基加合物转移至 AGT，修复来自烷化剂的 DNA 损伤。叶酸类似物 O(4)-苯甲酰叶酸（O(4)BF）是 AGT 的抑制剂，据报道其对肿瘤中α-叶酸受体具有选择性。我们在非人类灵长类动物模型中研究了 O(4)BF 的血浆和脑脊液（CSF）药代动力学和 CSF 穿透性。

方法

恒河猴（Macaca mulatta）接受静脉内 O(4)BF（10-50mg/kg），并获得连续的血液和 CSF 样本。通过 HPLC/光电二极管阵列测量血浆中的分析物浓度，并用 HPLC/MS/MS 测定 CSF 样本。

结果

在血浆和 CSF 中检测到 O(4)BF 的一种假定代谢物。O(4)BF 和代谢物以 0.04 mcM 的 ED(50)使纯化的 AGT 失活。O(4)BF 的中位清除率为 8ml/min/kg，半衰期为 1.1 小时。代谢物的半衰期明显更长（>20 小时），AUC 大于 O(4)BF。代谢物的 AUC 与 O(4)BF 的剂量不成比例地增加，表明消除呈饱和状态。O(4)BF 和其代谢物的 CSF 穿透性<1%。在 50mg/kg 剂量水平下，O(4)BF 在 CSF 中的 C(max)小于 0.09 mcM，而代谢物的 C(max)范围为 0.02 至 0.04 mcM（O(4)BF 等效物）。