Pharmacokinetics and distribution of SN 28049, a novel DNA binding anticancer agent, in mice.
OBJECTIVE
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 microM with a quantitation limit of 0.062 microM and a detection limit of 0.025 microM. 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 microM h) was also 693-fold greater than the plasma AUC, and considerably higher (approximately 5-fold) than any other tissue examined, indicating selective uptake and retention of SN 28049 in the tumour.


CONCLUSIONS
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.
Lukka
Pradeep B
PB
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Paxton
James W
JW
Kestell
Philip
P
Baguley
Bruce C
BC
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002853:Chromatography, Liquid; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009287:Naphthyridines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; C533598:N-(2-(dimethylamino)ethyl)-2,6-dimethyl-1-oxo-1,2-dihydroxybenzo(b)-1,6-naphthyridine-4-carboxamide; D009287:Naphthyridines; D059005:Topoisomerase II Inhibitors