Plasma and CNS pharmacokinetics of O4-benzylfolic acid (O 4BF) and metabolite in a non-human primate model

Meredith K. Chuk, Diane E. Cole, Cynthia McCully, Natalia A. Loktionova, Anthony Pegg, Robert J. Parker, Gary Pauly, Brigitte C. Widemann, Frank M. Balis, Elizabeth Fox

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1291-1297
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume67
Issue number6
DOIs
StatePublished - Jun 1 2011

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Pharmacokinetics
Metabolites
Primates
Cerebrospinal fluid
Plasmas
Acids
Cerebrospinal Fluid
Macaca mulatta
Area Under Curve
Half-Life
O(4)-benzylfolic acid
Folate Receptor 1
High Pressure Liquid Chromatography
Alkylating Agents
DNA
Guanine
Folic Acid
DNA Damage
Tumors
Assays

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Chuk, Meredith K. ; Cole, Diane E. ; McCully, Cynthia ; Loktionova, Natalia A. ; Pegg, Anthony ; Parker, Robert J. ; Pauly, Gary ; Widemann, Brigitte C. ; Balis, Frank M. ; Fox, Elizabeth. / Plasma and CNS pharmacokinetics of O4-benzylfolic acid (O 4BF) and metabolite in a non-human primate model. In: Cancer Chemotherapy and Pharmacology. 2011 ; Vol. 67, No. 6. pp. 1291-1297.
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title = "Plasma and CNS pharmacokinetics of O4-benzylfolic acid (O 4BF) and metabolite in a non-human primate model",
abstract = "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.",
author = "Chuk, {Meredith K.} and Cole, {Diane E.} and Cynthia McCully and Loktionova, {Natalia A.} and Anthony Pegg and Parker, {Robert J.} and Gary Pauly and Widemann, {Brigitte C.} and Balis, {Frank M.} and Elizabeth Fox",
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Chuk, MK, Cole, DE, McCully, C, Loktionova, NA, Pegg, A, Parker, RJ, Pauly, G, Widemann, BC, Balis, FM & Fox, E 2011, 'Plasma and CNS pharmacokinetics of O4-benzylfolic acid (O 4BF) and metabolite in a non-human primate model', Cancer Chemotherapy and Pharmacology, vol. 67, no. 6, pp. 1291-1297. https://doi.org/10.1007/s00280-010-1407-9

Plasma and CNS pharmacokinetics of O4-benzylfolic acid (O 4BF) and metabolite in a non-human primate model. / Chuk, Meredith K.; Cole, Diane E.; McCully, Cynthia; Loktionova, Natalia A.; Pegg, Anthony; Parker, Robert J.; Pauly, Gary; Widemann, Brigitte C.; Balis, Frank M.; Fox, Elizabeth.

In: Cancer Chemotherapy and Pharmacology, Vol. 67, No. 6, 01.06.2011, p. 1291-1297.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Plasma and CNS pharmacokinetics of O4-benzylfolic acid (O 4BF) and metabolite in a non-human primate model

AU - Chuk, Meredith K.

AU - Cole, Diane E.

AU - McCully, Cynthia

AU - Loktionova, Natalia A.

AU - Pegg, Anthony

AU - Parker, Robert J.

AU - Pauly, Gary

AU - Widemann, Brigitte C.

AU - Balis, Frank M.

AU - Fox, Elizabeth

PY - 2011/6/1

Y1 - 2011/6/1

N2 - 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.

AB - 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.

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