Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026

In this study we investigated the in vitro time dependence of radiosensitisation, pharmacokinetics and metabolism of NU7026, a novel inhibitor of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). At a dose of 10  μ M , which is nontoxic to cells per se , a minimum NU7026 exposure of 4 h i...

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Published in:British journal of cancer Vol. 93; no. 9; pp. 1011 - 1018
Main Authors: Nutley, B P, Smith, N F, Hayes, A, Kelland, L R, Brunton, L, Golding, B T, Smith, G C M, Martin, N M B, Workman, P, Raynaud, F I
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 31.10.2005
Nature Publishing Group
Subjects:
Animals
Ataxia
Biological and medical sciences
Biological Availability
Biomedical and Life Sciences
Biomedicine
Cancer Research
Cancer therapies
Cell Proliferation - drug effects
Cell Proliferation - radiation effects
Chromones - metabolism
Chromones - pharmacokinetics
DNA repair
DNA-Activated Protein Kinase - antagonists & inhibitors
Drug Evaluation, Preclinical
Drug Resistance
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacokinetics
Enzymes
Epidemiology
Female
Gamma Rays
Humans
Kinases
Medical research
Medical sciences
Metabolism
Metabolites
Mice
Mice, Inbred BALB C
Molecular Medicine
Morpholines - metabolism
Morpholines - pharmacokinetics
Oncology
Ovarian Neoplasms - metabolism
Ovarian Neoplasms - radiotherapy
Pharmacokinetics
Proteins
Radiation
Radiation Tolerance
Translational Therapeutics
Tumor Stem Cell Assay
Tumors
United Kingdom > UK
pharmacokinetics
metabolism
DNA-PK
NU7026
Cancerology
DNA
Inhibitor
Metabolism
Pharmacokinetics
ISSN:0007-0920, 1532-1827
Online Access:Get full text
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Summary:In this study we investigated the in vitro time dependence of radiosensitisation, pharmacokinetics and metabolism of NU7026, a novel inhibitor of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). At a dose of 10  μ M , which is nontoxic to cells per se , a minimum NU7026 exposure of 4 h in combination with 3 Gy radiation is required for a significant radiosensitisation effect in CH1 human ovarian cancer cells. Following intravenous administration to mice at 5 mg kg −1 , NU7026 underwent rapid plasma clearance (0.108 l h −1 ) and this was largely attributed to extensive metabolism. Bioavailability following interperitoneal (i.p.) and p.o. administration at 20 mg kg −1 was 20 and 15%, respectively. Investigation of NU7026 metabolism profiles in plasma and urine indicated that the compound undergoes multiple hydroxylations. A glucuronide conjugate of a bis-hydroxylated metabolite represented the major excretion product in urine. Identification of the major oxidation site as C-2 of the morpholine ring was confirmed by the fact that the plasma clearance of NU7107 (an analogue of NU7026 methylated at C-2 and C-6 of the morpholine ring) was four-fold slower than that of NU7026. The pharmacokinetic simulations performed predict that NU7026 will have to be administered four times per day at 100 mg kg −1 i.p. in order to obtain the drug exposure required for radiosensitisation.
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Currently at Antisoma plc, West Africa House, Hanger Lane, Ealing, London W5 3QR, UK.
Currently at the National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA
ISSN:0007-0920
1532-1827
DOI:10.1038/sj.bjc.6602823