Pharmacokinetics of deguelin, a cancer chemopreventive agent in rats.
OBJECTIVE
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.
Udeani
G O
GO
Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612-7230, USA.
Zhao
G M
GM
Shin
Y G
YG
Kosmeder
J W
JW
Beecher
C W
CW
Kinghorn
A D
AD
Moriarty
R M
RM
Moon
R C
RC
Pezzuto
J M
JM
D000818:Animals; D016588:Anticarcinogenic Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006207:Half-Life; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D016588:Anticarcinogenic Agents; D012402:Rotenone; C107676:deguelin