Plasma and CNS pharmacokinetics of O4-benzylfolic acid (O4BF) and metabolite in a non-human primate model.
Plasma and CNS pharmacokinetics of O4-benzylfolic acid (O4BF) and metabolite in a non-human primate model.
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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 CNS 药代动力学。
DOI：
10.1007/s00280-010-1407-9
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发表时间：
2011
影响因子：
3
通讯作者：
Fox,Elizabeth
中科院分区：
文献类型：
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作者：
Chuk,MeredithK;Cole,DianeE;McCully,Cynthia;Loktionova,NataliaA;Pegg,AnthonyE;Parker,RobertJ;Pauly,Gary;Widemann,BrigitteC;Balis,FrankM;Fox,Elizabeth
目的O 6-烷基鸟嘌呤-DNA烷基转移酶（AGT）通过将DNA中鸟嘌呤O 6-位上的烷基加合物转移到AGT上来修复烷化剂对DNA的损伤。叶酸类似物O 4-苄基叶酸（O 4 BF）是AGT的抑制剂，据报道在肿瘤中对α-叶酸受体具有选择性。我们研究了血浆和脑脊液（CSF）的药物动力学和O 4 BF在非人灵长类model.MethodsRhesus猴（Macaca mulatta）静脉注射O 4 BF（10-50 mg/kg），并获得了系列血液和CSF样品的CSF渗透。血浆中的分析物浓度测定HPLC/光电二极管阵列，和HPLC/MS/MS分析用于CSF samples.ResultsA推定的代谢产物O 4 BF检测血浆和CSF。O 4 BF及其代谢产物灭活纯化的AGT，ED 50为0.04 mcM。O 4 BF的中位清除率为8 ml/min/kg，半衰期为1.1 h。该代谢物的半衰期（>20 h）和AUC显著长于O 4 BF。代谢产物的AUC与O 4 BF剂量不成比例地增加，表明可饱和消除。O 4 BF及其代谢产物的脑脊液渗透率<1%。在50 mg/kg剂量水平下，O 4 BF的Cmaxin CSF小于0.09 mcM，代谢产物的Cmax范围为0.02 - 0.04 mcM结论脑脊液中O 4 BF及其代谢产物浓度超过AGT的ED 50;但是，在此情况下，最近报道缺乏受体特异性和药代动力学数据，表明O 4 BF及其代谢产物的饱和消除可能限制剂量-这种药物的升级和未来的临床开发。
PurposeO6-alkylguanine-DNA alkyltransferase (AGT) repairs DNA damage from alkylating agents by transferring the alkyl adducts from the O6-position of guanine in DNA to AGT. The folate analog O4-benzylfolic acid (O4BF) 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 O4BF in a non-human primate model.MethodsRhesus monkeys (Macaca mulatta)received O4BF (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.ResultsA putative metabolite of O4BF was detected in plasma and CSF. O4BF and the metabolite inactivated purified AGT with ED50of 0.04 mcM. The median clearance of O4BF 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 O4BF. The AUC of the metabolite increased disproportionately to the dose of O4BF, suggesting saturable elimination. CSF penetration of O4BF and its metabolite was < 1%. At the 50 mg/kg dose level, the Cmaxin CSF for O4BF was less than 0.09 mcM and for the metabolite the Cmaxranged from 0.02 to 0.04 mcM (O4BF equivalents).ConclusionsConcentrations of O4BF and the metabolite in CSF exceeded the ED50of AGT; however, recently reported lack of receptor specificity and pharmacokinetic data suggesting saturable elimination of both O4BF and its metabolite may limit dose-escalation and future clinical development of this agent.