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 (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.

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.

• Authors: G O Udeani, G M Zhao, Y G Shin, J W Kosmeder 2nd, C W Beecher, A D Kinghorn, R M Moriarty, R C Moon, J M Pezzuto
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 47 Issue 3 Pg. 263-8 (Mar 2001) ISSN: 0344-5704 [Print] Germany
• PMID: 11320671 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anticarcinogenic Agents
• Rotenone
• deguelin

Topics

• Animals
• Anticarcinogenic Agents (blood, pharmacokinetics)
• Area Under Curve
• Chromatography, High Pressure Liquid
• Female
• Half-Life
• Rats
• Rats, Sprague-Dawley
• Rotenone (analogs & derivatives, blood, pharmacokinetics)
• Tissue Distribution