warfarin and puerarin

The current study was conducted to investigate the potential pharmacokinetic and pharmacodynamic interactions between warfarin and puerarin which is the most abundant component in Pueraria lobata (Gegen). In vivo and ex vivo rat models were used to reveal the underlying mechanisms of such interactions.. Apart from one control group, five groups of Sprague-Dawley rats were treated with warfarin, oral puerarin, oral puerarin with warfarin, intravenous puerarin, intravenous puerarin with warfarin. The treatment lasted for 5 consecutive days. Thereafter, the levels of warfarin, warfarin metabolites and puerarin in plasma of these rats were monitored and compared. The rCyps activity and expression in rat livers of different treatment groups were assessed. The prothrombin time was observed. The vitamin K epoxide reductase (VKOR) activity and expression in rat livers were evaluated. Thrombomodulin activity and expression in the rat lung and rat plasma were assessed. The soluble thrombomodulin (sTM) concentrations of different treatment groups were examined.. Intravenously administered puerarin altered the pharmacokinetics of warfarin significantly by shortening t. Puerarin increased warfarin metabolism and offset warfarin anticoagulation by inducing rCyps, upregulating VKOR and inhibiting thrombomodulin in rats. The clinical impact of such potential interactions warrants further verification. Copyright © 2016 John Wiley & Sons, Ltd.

Topics: Administration, Intravenous; Administration, Oral; Animals; Anticoagulants; Cardiotonic Agents; Cytochrome P-450 Enzyme System; Drug Interactions; Isoflavones; Lung; Male; Microsomes, Liver; Prothrombin Time; Rats; Rats, Sprague-Dawley; Thrombomodulin; Up-Regulation; Vitamin K Epoxide Reductases; Warfarin

The present study was designed to determine the effects of puerarin pre-treatment on the pharmacokinetics of the oral anticoagulant agent warfarin and the antiplatelet agent clopidogrel in rats. In the treatment group, rats was gavaged with warfarin or clopidogrel after repeated treatment with puerarin at intraperitoneal doses of 20, 60, or 200 mg·kg(-1) for 7 days, while rats in the control group were administrated only with the same dose warfarin or clopidogrel. Plasma samples were obtained at the prescribed times and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). The results showed that rats treated with puerarin at all the test doses of 20, 60 and 200 mg·kg(-1) were found to affect the pharmacokinetics of warfarin, but not clopidogrel, suggesting a potential herb-drug interaction between puerarin and warfarin.

Topics: Animals; Anticoagulants; Chromatography, Liquid; Clopidogrel; Drug Administration Schedule; Herb-Drug Interactions; Injections, Intraperitoneal; Isoflavones; Male; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Tandem Mass Spectrometry; Ticlopidine; Vasodilator Agents; Warfarin

Puerarin is a widely used compound in Chinese traditional medicine and exhibits many pharmacological activities. Binding of puerarin to human serum albumin (HSA) was investigated by ultraviolet absorbance, fluorescence, circular dichroism and molecular docking. Puerarin caused a static quenching of intrinsic fluorescence of HSA, the quenching data was analyzed by Stern-Volmer equation. There was one primary puerarin binding site on HSA with a binding constant of 4.12 x 10(4) M(-1) at 298 K. Thermodynamic analysis by Van Hoff equation found enthalpy change (DeltaH(0)) and entropy change (DeltaS(0)) were -28.01 kJ/mol and -5.63 J/mol K respectively, which indicated the hydrogen bond and Van der Waas interaction were the predominant forces in the binding process. Competitive experiments showed a displacement of warfarin by puerarin, which revealed that the binding site was located at the drug site I. Puerarin was about 2.22 nm far from the tryptophan according to the observed fluorescence resonance energy transfer between HSA and puerarin. Molecular docking suggested the hydrophobic residues such as tyrosine (Tyr) 150, Tyr 148, Tyr 149 and polar residues such as lysine (Lys) 199, Lys 195, arginine 257 and histidine 242 played an important role in the binding reaction.

Topics: Binding, Competitive; Circular Dichroism; Humans; Hydrogen Bonding; Isoflavones; Molecular Structure; Protein Binding; Protein Conformation; Serum Albumin; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet; Thermodynamics; Warfarin