Pharmacokinetics of deguelin, a cancer chemopreventive agent in rats

• Published in: Cancer chemotherapy and pharmacology Vol. 47; no. 3; pp. 263 - 268
• Main Authors: UDEANI, George O, ZHAO, Guo-Min, YOUNG GEUN SHIN, KOSMEDER, Jerome W, BEECHER, Christopher W. W, KINGHORN, A. Douglas, MORIARTY, Robert M, MOON, Richard C, PEZZUTO, John M
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.03.2001
• Subjects: Animals; Anticarcinogenic Agents - blood; Anticarcinogenic Agents - pharmacokinetics; Area Under Curve; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Chemical agents; Chromatography, High Pressure Liquid; Female; Half-Life; Medical sciences; Rats; Rats, Sprague-Dawley; Rotenone - analogs & derivatives; Rotenone - blood; Rotenone - pharmacokinetics; Tissue Distribution; Tumors; Urine; Excretion; Intravenous administration; Rat; Metabolite; Rodentia; Malignant tumor; Anticarcinogen; Metabolism; Carcinogenesis; Biodistribution; Blood plasma; Prevention; Vertebrata; Mammalia; Treatment; Animal; Feces; Pharmacokinetics
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s002800000187

To study the pharmacokinetics of deguelin, a naturally occurring potential cancer chemopreventive agent, in rats. [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. Deguelin exhibited a mean residence time (MRT) of 6.98 h and terminal half-life (t1/2(gamma)) 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. 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.