Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026
| Autor: | N F Smith, Lloyd R. Kelland, Graeme C. M. Smith, Paul Workman, Niall Morrison Barr Martin, Bernard Nutley, Florence I. Raynaud, Angela Hayes, L. Brunton, Bernard T. Golding |
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| Rok vydání: | 2005 |
| Předmět: |
NU7026
Cancer Research Morpholines Metabolite Drug Evaluation Preclinical Biological Availability DNA-Activated Protein Kinase Urine Pharmacology Biology Radiation Tolerance DNA-PK Mice chemistry.chemical_compound Pharmacokinetics Morpholine Animals Humans Enzyme Inhibitors Tumor Stem Cell Assay Cell Proliferation Ovarian Neoplasms Mice Inbred BALB C Metabolism In vitro Bioavailability Oncology chemistry Chromones Gamma Rays Female Translational Therapeutics Glucuronide metabolism pharmacokinetics |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| DOI: | 10.1038/sj.bjc.6602823 |
| Popis: | 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 muM, 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. |
| Databáze: | OpenAIRE |
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