Comparison of a homologous series of benzonaphthyridine anti-cancer agents in mice

Divergence between tumour and plasma pharmacokinetics

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

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Purpose: N-[2-(dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]- 1,6-naphthyridine-4-carboxamide (SN 28049), a DNA-binding benzonaphthyridine, has shown curative activity against colon-38 adenocarcinoma after a single dose in mice. A homologous series of 5 compounds, where the 2-methyl group was replaced by a hydrogen, ethyl, propyl, or butyl, was used to evaluate the role of lipophilicity and tumour pharmacokinetics on their antitumour activity. Methods: All analogues were administered (25 μmol/kg) to healthy and tumour-bearing C57 Bl/6 mice and concentrations were measured in plasma, brain, heart, kidney, liver, lung, and tumour tissues. Microsomal stability studies were performed with mouse livers and plasma protein binding studies by equilibrium dialysis. Results: Plasma pharmacokinetics conformed to a model where increasing lipophilicity was associated with a decreasing area under the concentration-time curve (AUC), an increasing clearance and volume of distribution. In contrast, tumour pharmacokinetic parameters showed a very different relationship, where the AUC of the methyl derivative (2,334 μM h) was 89-fold higher than that of the hydrogen derivative (26.3 μM h), with other homologues having intermediate values. The tumour AUC correlated (r = -0.98, P = 2 × 10 -7) with the in vivo antitumour activity of this series. The methyl derivative had a 22 min microsomal half-life, while other analogues ranged from 1.6 to 12.2 min. The plasma-free fraction decreased (17-5 %) significantly with lipophilicity (r = 0.96, P = 2 × 10 -7). Conclusion: The plasma pharmacokinetics of this series is related to changes in drug lipophilicity. However, the tumour pharmacokinetics reveals a strong dependence on the nitrogen substituent on the benzonaphthyridine chromophore, with the methyl group providing by far the best tumour tissue retention.

Original languageEnglish (US)
Pages (from-to)151-160
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume70
Issue number1
DOIs
StatePublished - Jul 1 2012

Fingerprint

Pharmacokinetics
Tumors
Plasmas
Neoplasms
Derivatives
Liver
Hydrogen
Bearings (structural)
Naphthyridines
Tissue
Dialysis
Chromophores
Protein Binding
Half-Life
Blood Proteins
Brain
Colon
Adenocarcinoma
Nitrogen
Kidney

All Science Journal Classification (ASJC) codes

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

Cite this

Comparison of a homologous series of benzonaphthyridine anti-cancer agents in mice : Divergence between tumour and plasma pharmacokinetics. / Lukka, Pradeep B.; Paxton, James W.; Kestell, Philip; Baguley, Bruce C.

In: Cancer Chemotherapy and Pharmacology, Vol. 70, No. 1, 01.07.2012, p. 151-160.

Research output: Contribution to journalArticle

@article{e24fb028f17d4a95807e0ed9bfe4ef86,
title = "Comparison of a homologous series of benzonaphthyridine anti-cancer agents in mice: Divergence between tumour and plasma pharmacokinetics",
abstract = "Purpose: N-[2-(dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]- 1,6-naphthyridine-4-carboxamide (SN 28049), a DNA-binding benzonaphthyridine, has shown curative activity against colon-38 adenocarcinoma after a single dose in mice. A homologous series of 5 compounds, where the 2-methyl group was replaced by a hydrogen, ethyl, propyl, or butyl, was used to evaluate the role of lipophilicity and tumour pharmacokinetics on their antitumour activity. Methods: All analogues were administered (25 μmol/kg) to healthy and tumour-bearing C57 Bl/6 mice and concentrations were measured in plasma, brain, heart, kidney, liver, lung, and tumour tissues. Microsomal stability studies were performed with mouse livers and plasma protein binding studies by equilibrium dialysis. Results: Plasma pharmacokinetics conformed to a model where increasing lipophilicity was associated with a decreasing area under the concentration-time curve (AUC), an increasing clearance and volume of distribution. In contrast, tumour pharmacokinetic parameters showed a very different relationship, where the AUC of the methyl derivative (2,334 μM h) was 89-fold higher than that of the hydrogen derivative (26.3 μM h), with other homologues having intermediate values. The tumour AUC correlated (r = -0.98, P = 2 × 10 -7) with the in vivo antitumour activity of this series. The methyl derivative had a 22 min microsomal half-life, while other analogues ranged from 1.6 to 12.2 min. The plasma-free fraction decreased (17-5 {\%}) significantly with lipophilicity (r = 0.96, P = 2 × 10 -7). Conclusion: The plasma pharmacokinetics of this series is related to changes in drug lipophilicity. However, the tumour pharmacokinetics reveals a strong dependence on the nitrogen substituent on the benzonaphthyridine chromophore, with the methyl group providing by far the best tumour tissue retention.",
author = "Lukka, {Pradeep B.} and Paxton, {James W.} and Philip Kestell and Baguley, {Bruce C.}",
year = "2012",
month = "7",
day = "1",
doi = "10.1007/s00280-012-1892-0",
language = "English (US)",
volume = "70",
pages = "151--160",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - Comparison of a homologous series of benzonaphthyridine anti-cancer agents in mice

T2 - Divergence between tumour and plasma pharmacokinetics

AU - Lukka, Pradeep B.

AU - Paxton, James W.

AU - Kestell, Philip

AU - Baguley, Bruce C.

PY - 2012/7/1

Y1 - 2012/7/1

N2 - Purpose: N-[2-(dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]- 1,6-naphthyridine-4-carboxamide (SN 28049), a DNA-binding benzonaphthyridine, has shown curative activity against colon-38 adenocarcinoma after a single dose in mice. A homologous series of 5 compounds, where the 2-methyl group was replaced by a hydrogen, ethyl, propyl, or butyl, was used to evaluate the role of lipophilicity and tumour pharmacokinetics on their antitumour activity. Methods: All analogues were administered (25 μmol/kg) to healthy and tumour-bearing C57 Bl/6 mice and concentrations were measured in plasma, brain, heart, kidney, liver, lung, and tumour tissues. Microsomal stability studies were performed with mouse livers and plasma protein binding studies by equilibrium dialysis. Results: Plasma pharmacokinetics conformed to a model where increasing lipophilicity was associated with a decreasing area under the concentration-time curve (AUC), an increasing clearance and volume of distribution. In contrast, tumour pharmacokinetic parameters showed a very different relationship, where the AUC of the methyl derivative (2,334 μM h) was 89-fold higher than that of the hydrogen derivative (26.3 μM h), with other homologues having intermediate values. The tumour AUC correlated (r = -0.98, P = 2 × 10 -7) with the in vivo antitumour activity of this series. The methyl derivative had a 22 min microsomal half-life, while other analogues ranged from 1.6 to 12.2 min. The plasma-free fraction decreased (17-5 %) significantly with lipophilicity (r = 0.96, P = 2 × 10 -7). Conclusion: The plasma pharmacokinetics of this series is related to changes in drug lipophilicity. However, the tumour pharmacokinetics reveals a strong dependence on the nitrogen substituent on the benzonaphthyridine chromophore, with the methyl group providing by far the best tumour tissue retention.

AB - Purpose: N-[2-(dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]- 1,6-naphthyridine-4-carboxamide (SN 28049), a DNA-binding benzonaphthyridine, has shown curative activity against colon-38 adenocarcinoma after a single dose in mice. A homologous series of 5 compounds, where the 2-methyl group was replaced by a hydrogen, ethyl, propyl, or butyl, was used to evaluate the role of lipophilicity and tumour pharmacokinetics on their antitumour activity. Methods: All analogues were administered (25 μmol/kg) to healthy and tumour-bearing C57 Bl/6 mice and concentrations were measured in plasma, brain, heart, kidney, liver, lung, and tumour tissues. Microsomal stability studies were performed with mouse livers and plasma protein binding studies by equilibrium dialysis. Results: Plasma pharmacokinetics conformed to a model where increasing lipophilicity was associated with a decreasing area under the concentration-time curve (AUC), an increasing clearance and volume of distribution. In contrast, tumour pharmacokinetic parameters showed a very different relationship, where the AUC of the methyl derivative (2,334 μM h) was 89-fold higher than that of the hydrogen derivative (26.3 μM h), with other homologues having intermediate values. The tumour AUC correlated (r = -0.98, P = 2 × 10 -7) with the in vivo antitumour activity of this series. The methyl derivative had a 22 min microsomal half-life, while other analogues ranged from 1.6 to 12.2 min. The plasma-free fraction decreased (17-5 %) significantly with lipophilicity (r = 0.96, P = 2 × 10 -7). Conclusion: The plasma pharmacokinetics of this series is related to changes in drug lipophilicity. However, the tumour pharmacokinetics reveals a strong dependence on the nitrogen substituent on the benzonaphthyridine chromophore, with the methyl group providing by far the best tumour tissue retention.

UR - http://www.scopus.com/inward/record.url?scp=84863432502&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863432502&partnerID=8YFLogxK

U2 - 10.1007/s00280-012-1892-0

DO - 10.1007/s00280-012-1892-0

M3 - Article

VL - 70

SP - 151

EP - 160

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 1

ER -