Pharmacokinetics of a novel histone deacetylase inhibitor, apicidin, in rats

Abstract

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.

Quantitative Determination of Absorption and First-Pass Metabolism of Apicidin, a Potent Histone Deacetylase Inhibitor

“…In our pervious study, however, no saturable disposition was observed over the i.v. dose range of 0.5-4.0 mg/kg (Shin et al, 2006). The serum concentrations obtained after oral administration of 5 or 10 mg/kg in our present study were within the ranges of the observed serum concentrations in our previous study.…”

“…One of the sites responsible for potential extrahepatic metabolism is the lung (Heinemann and Fishman, 1969). The total systemic clearance of apicidin in conscious rat was reported to be 15.7 ml/min (Shin et al, 2006), which was significantly higher than the liver blood flow (11.9 ml/min) (Bernareggi and Rowland, 1991). The role of biliary and urinary excretion of apicidin seems to be minor as well (Shin et al, 2006).…”

“…The total systemic clearance of apicidin in conscious rat was reported to be 15.7 ml/min (Shin et al, 2006), which was significantly higher than the liver blood flow (11.9 ml/min) (Bernareggi and Rowland, 1991). The role of biliary and urinary excretion of apicidin seems to be minor as well (Shin et al, 2006). Therefore, an extrahepatic elimination such as pulmonary metabolism may be suspected.…”

“…Literature information on the pharmacokinetics of apicidin following i.v. and oral administration were available only from conscious rats (Shin et al, 2006). To compare the pharmacokinetics of apicidin under the same conditions, i.v.…”

“…However, only a few reports are available about the pharmacokinetic characteristics of apicidin. In our previous study, the oral bioavailability of apicidin was found to be 19.3% and 14.2% in fasting and nonfasting rats, respectively (Shin et al, 2006). A fundamental understanding of the absorption processes as well as the factors responsible for the relatively low oral bioavailability is critical for apicidin to be developed as an orally available chemotherapeutic agent.…”