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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Vydáno v:	British journal of cancer Ročník 93; číslo 9; s. 1011 - 1018
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 31.10.2005 Nature Publishing Group
Témata:	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
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 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