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

Nutley BP, Smith NF, Hayes A, Kelland LR, Brunton L, Golding BT, Smith GC, Martin NM, Workman P, Raynaud FI - Br. J. Cancer (2005)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton SM2 5NG, UK.

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.

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Related in: MedlinePlus

Time dependence of plasma concentration of NU7026 as measured by liquid chromatography tandem mass spectrometry following administration at 5 mg kg−1 i.v., 20 mg kg−1 i.p. and 50 mg kg−1 p.o. to mice. Female BALB/c mice were injected with 0.1 ml/10 g drug solution or vehicle. NU7026 was formulated in 10% DMSO and 5% Tween 20 in saline for i.p. and p.o. administion. For i.v. dosing at 5 mg kg−1, NU7026 was formulated in 10% ethanol, 25% PEG 200 and 5% Tween 20 in saline.
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fig3: Time dependence of plasma concentration of NU7026 as measured by liquid chromatography tandem mass spectrometry following administration at 5 mg kg−1 i.v., 20 mg kg−1 i.p. and 50 mg kg−1 p.o. to mice. Female BALB/c mice were injected with 0.1 ml/10 g drug solution or vehicle. NU7026 was formulated in 10% DMSO and 5% Tween 20 in saline for i.p. and p.o. administion. For i.v. dosing at 5 mg kg−1, NU7026 was formulated in 10% ethanol, 25% PEG 200 and 5% Tween 20 in saline.

Mentions: The plasma clearance of NU7026 following i.v. administration was rapid and the compound was undetectable at 4 h post administration (Figure 3, Table 1). Compound levels were above 10 μM for less than 1 h. Following i.p. administration at 20 mg kg−1, the time course of NU7026 in plasma was very similar to that observed after i.v. administration (Figure 3). Assuming linear pharmacokinetics following i.v. administration, the bioavailability by the i.p. route was 20%. Following oral administration with 50 mg kg−1, a maximum concentration of 2.2 μM was observed 1 h after administration. Based on linear i.v. pharmacokinetics, the oral bioavailability was calculated as 15%.


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

Nutley BP, Smith NF, Hayes A, Kelland LR, Brunton L, Golding BT, Smith GC, Martin NM, Workman P, Raynaud FI - Br. J. Cancer (2005)

Time dependence of plasma concentration of NU7026 as measured by liquid chromatography tandem mass spectrometry following administration at 5 mg kg−1 i.v., 20 mg kg−1 i.p. and 50 mg kg−1 p.o. to mice. Female BALB/c mice were injected with 0.1 ml/10 g drug solution or vehicle. NU7026 was formulated in 10% DMSO and 5% Tween 20 in saline for i.p. and p.o. administion. For i.v. dosing at 5 mg kg−1, NU7026 was formulated in 10% ethanol, 25% PEG 200 and 5% Tween 20 in saline.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361671&req=5

fig3: Time dependence of plasma concentration of NU7026 as measured by liquid chromatography tandem mass spectrometry following administration at 5 mg kg−1 i.v., 20 mg kg−1 i.p. and 50 mg kg−1 p.o. to mice. Female BALB/c mice were injected with 0.1 ml/10 g drug solution or vehicle. NU7026 was formulated in 10% DMSO and 5% Tween 20 in saline for i.p. and p.o. administion. For i.v. dosing at 5 mg kg−1, NU7026 was formulated in 10% ethanol, 25% PEG 200 and 5% Tween 20 in saline.
Mentions: The plasma clearance of NU7026 following i.v. administration was rapid and the compound was undetectable at 4 h post administration (Figure 3, Table 1). Compound levels were above 10 μM for less than 1 h. Following i.p. administration at 20 mg kg−1, the time course of NU7026 in plasma was very similar to that observed after i.v. administration (Figure 3). Assuming linear pharmacokinetics following i.v. administration, the bioavailability by the i.p. route was 20%. Following oral administration with 50 mg kg−1, a maximum concentration of 2.2 μM was observed 1 h after administration. Based on linear i.v. pharmacokinetics, the oral bioavailability was calculated as 15%.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton SM2 5NG, UK.

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.

Show MeSH
Related in: MedlinePlus