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

Lookup NU author(s): Dr Alastair Hayes, Professor Bernard Golding

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Abstract

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 μM, 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. © 2005 Cancer Research UK.


Publication metadata

Author(s): Nutley BP, Smith NF, Hayes A, Kelland LR, Brunton L, Golding BT, Smith GCM, Martin NMB, Workman P, Raynaud FI

Publication type: Article

Publication status: Published

Journal: British Journal of Cancer

Year: 2005

Volume: 93

Issue: 9

Pages: 1011-1018

ISSN (print): 0007-0920

ISSN (electronic): 1532-1827

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/sj.bjc.6602823

DOI: 10.1038/sj.bjc.6602823

PubMed id: 16249792


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