Pharmacokinetics and distribution of SN 28049, a novel DNA binding anticancer agent, in mice

Bhanu Pradeep Lukka, James W. Paxton, Philip Kestell, Bruce C. Baguley

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Abstract

Purpose N-[2-(Dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1, 2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide (SN 28049) is a potent DNA binding topoisomerase II poison that shows excellent antitumour activity in a colon-38 murine tumour model in comparison to standard topoisomerase II poisons. We report here the preclinical pharmacokinetics of SN 28049. Methods C57 Bl/6 mice (n = 3 per time point) were treated with a single i.v., i.p. or p.o. administration (8.9 mg/kg). Plasma and tissue samples were analysed using a validated LC/MS method utilizing a homologue as an internal standard. Results The assay range was 0.062-2.5 μM with a quantitation limit of 0.062 μM and a detection limit of 0.025 μM. Acceptable intra-and inter-assay accuracy (95-105%) and precision (<6.5% RSD) were achieved. Following i.v. administration, SN 28049 demonstrated 2-compartment model kinetics with a volume of distribution of 42.3 ± 4.1 l/kg, a plasma clearance of 12.1 ± 0.5 l/h per kg and distribution and elimination half-lives of 0.15 ± 0.02 and 2.8 ± 0.2 h (mean ± SE), respectively. For all administration routes, SN 28049 concentrations in normal tissues (brain, heart, liver, lung, and kidney) were 12-to 120-fold higher than those in plasma, but half-lives and mean residence times were similar. The i.p. and p.o. bioavailabilities were 83.1 ± 1.5 and 54.5 ±1.1%, respectively. In the tumour tissue, elimination half-life (9.1 ±0.7h) and the mean residence time (18.2 ± 0.7 h) were significantly (P < 0.001) longer than those of plasma and normal tissues. The tumour area under the concentration-time curve (AUC) (1,316 ± 66 μMh) was also 693-fold greater than the plasma AUC, and considerably higher (∼5-fold) than any other tissue examined, indicating selective uptake and retention of SN 28049 in the tumour. Conclusion We conclude that SN 28049's high tumour exposure and long tumour retention time is likely to contribute to its high antitumour activity in vivo.

Original languageEnglish (US)
Pages (from-to)1145-1152
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume65
Issue number6
DOIs
StatePublished - May 1 2010

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Pharmacokinetics
Antineoplastic Agents
Tumors
Tissue
DNA
Plasmas
Neoplasms
Type II DNA Topoisomerase
Poisons
Assays
Naphthyridines
Liver
Biological Availability
Half-Life
Limit of Detection
N-(2-(dimethylamino)ethyl)-2,6-dimethyl-1-oxo-1,2-dihydroxybenzo(b)-1,6-naphthyridine-4-carboxamide
Brain
Colon
Kidney
Lung

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Pharmacokinetics and distribution of SN 28049, a novel DNA binding anticancer agent, in mice. / Lukka, Bhanu Pradeep; Paxton, James W.; Kestell, Philip; Baguley, Bruce C.

In: Cancer Chemotherapy and Pharmacology, Vol. 65, No. 6, 01.05.2010, p. 1145-1152.

Research output: Contribution to journalArticle

Lukka, Bhanu Pradeep ; Paxton, James W. ; Kestell, Philip ; Baguley, Bruce C. / Pharmacokinetics and distribution of SN 28049, a novel DNA binding anticancer agent, in mice. In: Cancer Chemotherapy and Pharmacology. 2010 ; Vol. 65, No. 6. pp. 1145-1152.
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abstract = "Purpose N-[2-(Dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1, 2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide (SN 28049) is a potent DNA binding topoisomerase II poison that shows excellent antitumour activity in a colon-38 murine tumour model in comparison to standard topoisomerase II poisons. We report here the preclinical pharmacokinetics of SN 28049. Methods C57 Bl/6 mice (n = 3 per time point) were treated with a single i.v., i.p. or p.o. administration (8.9 mg/kg). Plasma and tissue samples were analysed using a validated LC/MS method utilizing a homologue as an internal standard. Results The assay range was 0.062-2.5 μM with a quantitation limit of 0.062 μM and a detection limit of 0.025 μM. Acceptable intra-and inter-assay accuracy (95-105{\%}) and precision (<6.5{\%} RSD) were achieved. Following i.v. administration, SN 28049 demonstrated 2-compartment model kinetics with a volume of distribution of 42.3 ± 4.1 l/kg, a plasma clearance of 12.1 ± 0.5 l/h per kg and distribution and elimination half-lives of 0.15 ± 0.02 and 2.8 ± 0.2 h (mean ± SE), respectively. For all administration routes, SN 28049 concentrations in normal tissues (brain, heart, liver, lung, and kidney) were 12-to 120-fold higher than those in plasma, but half-lives and mean residence times were similar. The i.p. and p.o. bioavailabilities were 83.1 ± 1.5 and 54.5 ±1.1{\%}, respectively. In the tumour tissue, elimination half-life (9.1 ±0.7h) and the mean residence time (18.2 ± 0.7 h) were significantly (P < 0.001) longer than those of plasma and normal tissues. The tumour area under the concentration-time curve (AUC) (1,316 ± 66 μMh) was also 693-fold greater than the plasma AUC, and considerably higher (∼5-fold) than any other tissue examined, indicating selective uptake and retention of SN 28049 in the tumour. Conclusion We conclude that SN 28049's high tumour exposure and long tumour retention time is likely to contribute to its high antitumour activity in vivo.",
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T1 - Pharmacokinetics and distribution of SN 28049, a novel DNA binding anticancer agent, in mice

AU - Lukka, Bhanu Pradeep

AU - Paxton, James W.

AU - Kestell, Philip

AU - Baguley, Bruce C.

PY - 2010/5/1

Y1 - 2010/5/1

N2 - Purpose N-[2-(Dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1, 2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide (SN 28049) is a potent DNA binding topoisomerase II poison that shows excellent antitumour activity in a colon-38 murine tumour model in comparison to standard topoisomerase II poisons. We report here the preclinical pharmacokinetics of SN 28049. Methods C57 Bl/6 mice (n = 3 per time point) were treated with a single i.v., i.p. or p.o. administration (8.9 mg/kg). Plasma and tissue samples were analysed using a validated LC/MS method utilizing a homologue as an internal standard. Results The assay range was 0.062-2.5 μM with a quantitation limit of 0.062 μM and a detection limit of 0.025 μM. Acceptable intra-and inter-assay accuracy (95-105%) and precision (<6.5% RSD) were achieved. Following i.v. administration, SN 28049 demonstrated 2-compartment model kinetics with a volume of distribution of 42.3 ± 4.1 l/kg, a plasma clearance of 12.1 ± 0.5 l/h per kg and distribution and elimination half-lives of 0.15 ± 0.02 and 2.8 ± 0.2 h (mean ± SE), respectively. For all administration routes, SN 28049 concentrations in normal tissues (brain, heart, liver, lung, and kidney) were 12-to 120-fold higher than those in plasma, but half-lives and mean residence times were similar. The i.p. and p.o. bioavailabilities were 83.1 ± 1.5 and 54.5 ±1.1%, respectively. In the tumour tissue, elimination half-life (9.1 ±0.7h) and the mean residence time (18.2 ± 0.7 h) were significantly (P < 0.001) longer than those of plasma and normal tissues. The tumour area under the concentration-time curve (AUC) (1,316 ± 66 μMh) was also 693-fold greater than the plasma AUC, and considerably higher (∼5-fold) than any other tissue examined, indicating selective uptake and retention of SN 28049 in the tumour. Conclusion We conclude that SN 28049's high tumour exposure and long tumour retention time is likely to contribute to its high antitumour activity in vivo.

AB - Purpose N-[2-(Dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1, 2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide (SN 28049) is a potent DNA binding topoisomerase II poison that shows excellent antitumour activity in a colon-38 murine tumour model in comparison to standard topoisomerase II poisons. We report here the preclinical pharmacokinetics of SN 28049. Methods C57 Bl/6 mice (n = 3 per time point) were treated with a single i.v., i.p. or p.o. administration (8.9 mg/kg). Plasma and tissue samples were analysed using a validated LC/MS method utilizing a homologue as an internal standard. Results The assay range was 0.062-2.5 μM with a quantitation limit of 0.062 μM and a detection limit of 0.025 μM. Acceptable intra-and inter-assay accuracy (95-105%) and precision (<6.5% RSD) were achieved. Following i.v. administration, SN 28049 demonstrated 2-compartment model kinetics with a volume of distribution of 42.3 ± 4.1 l/kg, a plasma clearance of 12.1 ± 0.5 l/h per kg and distribution and elimination half-lives of 0.15 ± 0.02 and 2.8 ± 0.2 h (mean ± SE), respectively. For all administration routes, SN 28049 concentrations in normal tissues (brain, heart, liver, lung, and kidney) were 12-to 120-fold higher than those in plasma, but half-lives and mean residence times were similar. The i.p. and p.o. bioavailabilities were 83.1 ± 1.5 and 54.5 ±1.1%, respectively. In the tumour tissue, elimination half-life (9.1 ±0.7h) and the mean residence time (18.2 ± 0.7 h) were significantly (P < 0.001) longer than those of plasma and normal tissues. The tumour area under the concentration-time curve (AUC) (1,316 ± 66 μMh) was also 693-fold greater than the plasma AUC, and considerably higher (∼5-fold) than any other tissue examined, indicating selective uptake and retention of SN 28049 in the tumour. Conclusion We conclude that SN 28049's high tumour exposure and long tumour retention time is likely to contribute to its high antitumour activity in vivo.

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