Purpose: O6-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 (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 O 4BF in a non-human primate model. Methods: Rhesus 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. Results: A putative metabolite of O4BF was detected in plasma and CSF. O4BF and the metabolite inactivated purified AGT with ED 50 of 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 Cmax in CSF for O4BF was less than 0.09 mcM and for the metabolite the C max ranged from 0.02 to 0.04 mcM (O4BF equivalents). Conclusions: Concentrations of O4BF and the metabolite in CSF exceeded the ED50 of 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.
All Science Journal Classification (ASJC) codes
- Cancer Research
- Pharmacology (medical)