Pharmacokinetic and pharmacodynamic model for ferulic acid in rabbits

• Main Authors: Li Yi-Chi, 李逸琦
• Other Authors: Ho Yi
• Format: Others
• Language: zh-TW
• Published: 2002
• Online Access: http://ndltd.ncl.edu.tw/handle/20149424888733173650

碩士 === 台北醫學院 === 藥學研究所 === 90 === Ferulic acid is a plant-food-derived antioxidants with hydroxy -cinnamate structure. It is wildly occurring in many kinds of fruits, vegetables, berries and grains. Ferulic acid has been studied on their biological potential to protect against various inflammatory related diseases. It also has obvious anticoagulant effect. However, it is still lack of about the pharmacokinetic reports of ferulic acid. The aims of this study were to investigate the pharmacokinetics and pharmacodynamic model of ferulic acid in the rabbits. The plasma concentrations of ferulic acid were determined by an accuracy and simple HPLC method consisted of a reverse phase column with UV detection at 320 nm. The calibration curve of plasma sample shows good linearity with in the concentration range of 0.01 to 50 mg/ml. The coefficients of validation (C.V) of the with-run and between-run validation were all within 10%. The recovery of analytical process in plasma was found to be 95.65%. The stability of ferulic acid in various pH buffer solutions was investigated. The result shows that ferulic acid was very stable in pH 2.62~pH 5.10 at room temperature (25oC), but at pH 6.66~pH 9.62 it would degrade progressively after six hours. Ferulic acid was given intravenously with dose of 5,10,25,75 mg/kg and oral 50 mg/kg, to six male New Zealand white rabbits. The pharmacokinetics of ferulic acid after intravenous administration at dose 5-25 mg/kg in rabbits can be described with two-compartment model. There were no significant different in elimination half-life and systemic clearance under these three doses. It results in a linear pharmacokinteics of ferulic acid in rabbits. After the intravenous administration dose of 75 mg/kg the concentration-time profiles can be fitted to two compartments. But the distribution and elimination phase are changed by the dose-dependent pharmacokinetics. After the oral administration of the dose 50 mg/kg of ferulic acid to rabbits, the plasma concentration-time profiles could be fitted by a two-compartment model. The mean absolute bioavailability of ferulic acid was estimated of 0.75±0.07 by using the value of AUC following the intravenous administration dose of 25 mg/kg. The pharmacodynamic effects of ferulic acid were measured from its anticoagulant response. Three kinds of anticoagulant effects such as BT (bleeding time), TT (thrombin time), PT (prothrombin time) and APTT (activated partial thromboplastin time) were measured. A series of in vitro experiments proved an anticoagulant of ferulic acid, measured by aPTT and PT. When the ferulic acid concentration in plasma was over the 7μg/ml, the aPTT was prolonged but the PT was normal. The prolongation of aPTT is seen with several deficiencies of the factors in intrinsic and common pathway. In this the animal experiment, three male New Zealand white rabbits were used. No matter intravenous administration 25, 75 mg/kg and oral administration 50mg/kg of ferulic acid were gived to rabbits, the prolongation effects of BT, aPTT and PT can be determination. In addition, 25 mg/kg of ferulic acid intravenous administration to rabbits, the PT had not prolongation. In 50 mg/kg, 75 mg/kg of ferulic acid was oral and intravenous administration, the PT have prolongation. It may possible have a high plasma concentration due to a high dose of ferulic acid. The factors of Ⅰ,Ⅱ,Ⅴ,Ⅹ just can be inhibition, and lead to PT prolongation. There is no direct relationship existed between the plasma concentration and the clotting time. But we can explain correlation of pharmacokinetic/ pharmacodynamic at the steady-state plasma concentration. Steady-state plasma concentration lower than 7μg/ml potency will disappear. Therefor 7μg/ml is minimum effective drug concentration. Prolonged of BT, aPTT and PT was not observed at peak concentration (Cmax) after oral administration and at distribution phase end after intravenous administration of ferulic acid. So we can suggest that, the anticoagulant effects were occurred when the ferulic acid was distributing through out in the body.