The effect of 1-furan-2-yl-3-pyridine-2-yl-propenone on pharmacokinetic parameters of warfarin.
1-Furan-2-yl-3-pyridine-2-yl-propenone (FPP-3) is an investigatory drug which has a dual inhibitory action on cyclooxygenase (COX) and 5-lipoxygenase (5-LOX). We examined its effect on the pharmacokinetics of warfarin. Three consecutive days of pretreatment with 17 mg/kg of FPP-3 had no significant effect on the pharmacokinetic parameters of warfarin when orally administered to rats. A higher dosage of FPP-3 however, did cause significant changes in the pharmacokinetic parameters of wafarin. The cytochrome P450 activity test demonstrated that the metabolism of R-warfarin was significantly inhibited by FPP-3 while there was little or no inhibition of the metabolism of S-warfarin, which is mainly responsible for its anticoagulant effect. Therefore, it appears that the alteration in the pharmacokinetic parameters of warfarin was due to the inhibitory effect of FPP-3 on the metabolism of R-warfarin. Although there was a significant increase in the plasma concentration, the area under the curve, half life of warfarin, and prothrombin time were not significantly changed. Based on these findings, the pharmacokinetic drug interaction between FPP-3 and warfarin mainly involves R-warfarin and, therefore, this interaction may not be of clinical significance in terms of warfarin-related toxicity.
Shanmugam
Srinivasan
S
College of Pharmacy, Yeungnam University, 214-1 Dae-dong, Kyungsan, Kyungbuk 712-749, Korea.
Lee
Eung Seok
ES
Jeong
Tae Cheon
TC
Yong
Chul Soon
CS
Choi
Han-Gon
HG
Woo
Jong-Soo
JS
Yoo
Bong Kyu
BK
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D003580:Cytochromes; D004347:Drug Interactions; D005663:Furans / Q000494:pharmacology*; D006207:Half-Life; D008297:Male; D011407:Propane / Q000031:analogs & derivatives* / Q000494:pharmacology; D011517:Prothrombin Time; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014859:Warfarin / Q000097:blood / Q000493:pharmacokinetics*
C508534:1-furan-2-yl-3-pyridin-2-yl-propenone; D000925:Anticoagulants; D016861:Cyclooxygenase Inhibitors; D003580:Cytochromes; D005663:Furans; D011725:Pyridines; D014859:Warfarin; C017170:Cyp1a2 protein, rat; D019388:Cytochrome P-450 CYP1A2; D011407:Propane