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


CONCLUSIONS
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.
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Pradeep B
PB
Lukka
James W
JW
Paxton
Philip
P
Kestell
Bruce C
BC
Baguley
D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D003110:Colonic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D009206:Myocardium / Q000378:metabolism; D009287:Naphthyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D016896:Treatment Outcome
C533598:N-(2-(dimethylamino)ethyl)-2,6-dimethyl-1-oxo-1,2-dihydroxybenzo(b)-1,6-naphthyridine-4-carboxamide; D009287:Naphthyridines