Pharmacokinetics of a novel histone deacetylase inhibitor, apicidin, in rats.
This study is the first report of the pharmacokinetics of a novel histone deacetylase inhibitor, apicidin, in rats after i.v. and oral administration. Apicidin was injected intravenously at doses of 0.5, 1.0, 2.0 and 4.0 mg/kg. The terminal elimination half-life (t1/2), systemic clearance (Cl) and steady-state volume of distribution (Vss) remained unaltered as a function of dose, with values in the range 0.8-1.1 h, 59.6-68.0 ml/min/kg and 2.4-2.7 l/kg, respectively. Whereas, the initial serum concentration (C0) and AUC increased linearly as the dose was increased. Taken together, the pharmacokinetics of apicidin were linear over the i.v. dose range studied. The extent of urinary and biliary excretion of apicidin was minimal (0.017%-0.020% and 0.049% +/- 0.016%, respectively). Oral pharmacokinetic studies were conducted in fasting and non-fasting groups of rats at a dose of 10 mg/kg. The Tmax, Cl/F and Vz/F were in the range 0.9-1.1 h, 520.3-621.2 ml/min/kg and 67.6-84.4 l/kg, respectively. No significant difference was observed in the oral absorption profiles between the two groups of rats. Apicidin was poorly absorbed, with the absolute oral bioavailability of 19.3% and 14.2% in fasting and non-fasting rats.
Shin
Beom Soo
BS
College of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon, Kyeonggi-do, 440-746, Korea.
Chang
Hyun Sook
HS
Park
Eun Hye
EH
Yoon
Chi Ho
CH
Kim
Hye Youn
HY
Kim
John
J
Ryu
Jae Kuk
JK
Zee
Ok Pyo
OP
Lee
Kang Choon
KC
Cao
Dianxiu
D
Yoo
Sun Dong
SD
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005215:Fasting / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D007275:Injections, Intravenous; D016014:Linear Models; D008297:Male; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C102351:apicidin