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.
journal_name
Chemotherapyjournal_title
Chemotherapyauthors
Shin BS,Bulitta JB,Hong DK,Kim HY,Kim MK,Choi Y,Lee JB,Hwang SW,Lee MH,Yoo SDdoi
10.1159/000328027subject
Has Abstractpub_date
2011-01-01 00:00:00pages
259-67issue
3eissn
0009-3157issn
1421-9794pii
000328027journal_volume
57pub_type
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