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

Abstract

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.