Population pharmacokinetics of a novel histone deacetylase inhibitor, cyclo{(2S)-2-amino-8-[(aminocarbonyl)hydrazono] decanoyl-1-L-tryptophyl-L-isoleucyl-(2R)-2-piperidinecarbonyl} (SD-2007), and its metabolic conversion to apicidin after intravenous injection and oral administration in rats.

Background: This study assessed the population pharmacokinetics and metabolic conversion of a novel histone deacetylase (HDAC) inhibitor, SD-2007, into its active metabolite, apicidin, in rats. Methods: SD-2007 was given to rats by intravenous injection (4 mg/kg) and oral administration (40 mg/kg). Serum concentrations of SD-2007 and apicidin were determined by LC-MS/MS. All concentrations were analyzed using a population pharmacokinetic model with 9 compartments in S-ADAPT. Results: The area under the curve for apicidin was 96 +/- 16 mg.h/ml after 4 mg/kg administered intravenously and 2,455 +/- 1,211 mg.h/ml after 40 mg/kg given orally. The population pharmacokinetic model described all profiles well. After oral administration of SD-2007, the median absolute bioavailability of SD-2007 was 6.67% (range 3.83-9.89) and the median apparent bioavailability was 22.3% (range 15.7-35.8) for apicidin, whereas only a median of 8.85% (range 7.57-9.34) of an intravenous SD-2007 dose was converted to apicidin. Conclusions: Oral SD-2007 displayed a substantial presystemic metabolism to active apicidin. The high serum concentrations of apicidin after oral administration of SD-2007 may cause significant HDAC inhibition. Copyright (C) 2011 S. Karger AG, Basel