ArticleCancer chemotherapy and pharmacology2011
Plasma and CNS pharmacokinetics of O4-benzylfolic acid (O4BF) and metabolite in a non-human primate model.
Article in Cancer chemotherapy and pharmacology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
1 citing paper in PubMed, 1 citations in OpenAlex.
- Multifaceted roles of alkyltransferase and related proteins in DNA repair, DNA damage, resistance to chemotherapy, and research tools.Chemical research in toxicology · 2011Review
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Authors and funding
10 authors at 6 institutions in 1 country.
Funding
Abstract
purposeO(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.
methodsRhesus 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.
resultsA 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).
conclusionsConcentrations 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.
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