title: Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026.
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 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.
authors.affiliation: Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton SM2 5NG, UK.
authors.forename: B P
authors.initials: BP
authors.lastname: Nutley
authors.forename: N F
authors.initials: NF
authors.lastname: Smith
authors.forename: A
authors.initials: A
authors.lastname: Hayes
authors.forename: L R
authors.initials: LR
authors.lastname: Kelland
authors.forename: L
authors.initials: L
authors.lastname: Brunton
authors.forename: B T
authors.initials: BT
authors.lastname: Golding
authors.forename: G C M
authors.initials: GC
authors.lastname: Smith
authors.forename: N M B
authors.initials: NM
authors.lastname: Martin
authors.forename: P
authors.initials: P
authors.lastname: Workman
authors.forename: F I
authors.initials: FI
authors.lastname: Raynaud
mesh_terms: D000818:Animals; D001682:Biological Availability; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002867:Chromones / Q000378:metabolism* / Q000493:pharmacokinetics*; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics*; D005260:Female; D005720:Gamma Rays; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000378:metabolism* / Q000493:pharmacokinetics*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000532:radiotherapy; D011836:Radiation Tolerance; D014410:Tumor Stem Cell Assay
chemical_list: C479235:2-(morpholin-4-yl)benzo(h)chromen-4-one; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D051747:DNA-Activated Protein Kinase