Plasma and CNS pharmacokinetics of O4-benzylfolic acid (O4BF) and metabolite in a non-human primate model.
OBJECTIVE
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.
Chuk
Meredith K
MK
Pediatric Oncology Branch, National Cancer Institute, 10 Center Drive, Building 10/Rm 1W-5750, Bethesda, MD 20892, USA. chukmk@gmail.com
Cole
Diane E
DE
McCully
Cynthia
C
Loktionova
Natalia A
NA
Pegg
Anthony E
AE
Parker
Robert J
RJ
Pauly
Gary
G
Widemann
Brigitte C
BC
Balis
Frank M
FM
Fox
Elizabeth
E
D000818:Animals; D001921:Brain / Q000378:metabolism*; D005492:Folic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D008253:Macaca mulatta; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors*
C524118:O(4)-benzylfolic acid; D005492:Folic Acid; D019853:O(6)-Methylguanine-DNA Methyltransferase