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Comparison of a homologous series of benzonaphthyridine anti-cancer agents in mice: divergence between tumour and plasma pharmacokinetics

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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), 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.

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Acknowledgments

This study was supported by the Auckland Cancer Society and Auckland Uniservices Ltd., New Zealand. We would like to thank Dr. Jagdish Jaiswal for his help in setting up the high throughput plasma protein binding study.

Conflict of interest

None.

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Authors and Affiliations

  1. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand

    Pradeep B. Lukka, Philip Kestell & Bruce C. Baguley

  2. Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand

    Pradeep B. Lukka & James W. Paxton

Authors
  1. Pradeep B. Lukka
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  2. James W. Paxton
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  3. Philip Kestell
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  4. Bruce C. Baguley
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Correspondence to Bruce C. Baguley.

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Lukka, P.B., Paxton, J.W., Kestell, P. et al. Comparison of a homologous series of benzonaphthyridine anti-cancer agents in mice: divergence between tumour and plasma pharmacokinetics. Cancer Chemother Pharmacol 70, 151–160 (2012). https://doi.org/10.1007/s00280-012-1892-0

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  • DOI: https://doi.org/10.1007/s00280-012-1892-0

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