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

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.

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.

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 ± 0.7 h) 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 μM h) 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.