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

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

Author information

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

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.

PMID:
20725726
[PubMed - indexed for MEDLINE]
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