Pharmacokinetics of deguelin, a cancer chemopreventive agent in rats

Abstract.

Purpose: To study the pharmacokinetics of deguelin, a naturally occurring potential cancer chemopreventive agent, in rats. Methods: [³H]Deguelin was administered intravenously (i.v.) under anesthesia, and blood samples were collected over 24 h. [³H]Deguelin and metabolites were extracted from plasma with ethyl acetate, and quantified by HPLC. Data were analyzed with the WinNolin pharmacokinetic software package to determine pharmacokinetic parameters. A three-compartment first-order elimination model was used to fit the plasma concentration-time curve. In addition, deguelin concentrations in tissues after i.v. and intragastric (i.g.) administration were determined by HPLC, and excretion (feces and urine) was evaluated over a 5-day period after i.g. administration. Results: Deguelin exhibited a mean residence time (MRT) of 6.98 h and terminal half-life (t_1/2(γ)) of 9.26 h. The area under the curve (AUC) and total clearance (Cl) were 57.3 ng·h/ml and 4.37 l/h per kg, respectively, with an apparent volume of distribution (V) and volume of distribution at steady-state (Vss) of 3.421 l/kg and 30.46 l/kg, respectively. Following i.v. administration, the relative levels of tissue distribution were as follows: heart>fat>mammary gland>colon>liver>kidney>brain>lung. Following i.g. administration, the relative levels of tissue distribution were as follows: perirenal fat>heart>mammary gland>colon>kidney>liver>lung>brain>skin. Within 5 days of i.g. administration, about 58.1% of the [³H]deguelin was eliminated via the feces and 14.4% via the urine. Approximately 1.7% of unchanged deguelin was found in the feces, and 0.4% in the urine. Conclusions: An initial pharmacokinetic investigation of deguelin showed that this rotenoid has a relatively long MRT and half-life in plasma in the rat. The compound distributed in the tissues and excreted as metabolites, mainly via the feces.