| Hesperidin is a flavanone glycoside consisting of hesperetin aglycon and disaccharide rutinose. Hesperidin and hesperetin both have multiple biological activities such as anti-inflammatory, antitumor, anti-oxidant, immunoregulation and therapeutical effect towards chronic venous insufficeincy. But the difficulty with hesperidin is low bioavailability (<25%). Hesperetin needs frequent drug administration to keep the level of plasma concentraion, because of its short biological half-life period and fast elimination after oral administration, which limits their clinical application. In our previous studies, in order to overcome the disadvantages above, a series of hesperidin derivatives were synthesized and the anti-inflammatory activity was evaluated. It was found that equimolar TAHP which synthetized through the acylation reaction exhibited more effective anti-rheumatic activity than its parent compound hesperidin in the AA rat model. The experiment studied the pharmacokinetics of TAHP and evaluated the synthetic drug reasonably, amied at providing information and guidance of new drug design and preclinical study. The main contents are summarized as follows:1The Synthesis and Purification of TAHPTAHP was synthetized through the acylation reaction using hesperetin as a starting material. The pure products were obtained by adsorption of active carbon and crystallization. The purity of TAHP was>98%(area normalization method). 2The establishment of analytical method of TAHP in biological matrixIt was found that hesperetin in the rat plasma solely in the experiment, while TAHP was unable to detect after administration. So we determined hesperetin to report the absorption of TAHP. Plasma sample was prepared by incubating with β-glucuronidase and extracted by ethyl acetate. HPLC method was developed to determine the concentration of TAHP and hesperetin—active metabolite of TAHP in biological spocime. The colmnn was Elite Hypersil QDS C18(4.6mm×200mm,5μm). The mobile phase consisting of methyl alcohol-0.5%glacial acetic acid was run at a gradient elution (0～20min,41:59～41:59;20～30min,41:59～65:35;30-35min,65:35～41:59) with a flow rate of1.0ml·min-1. The detection wavelength was set at288nm. The chromatographic column temperatures was40℃. The chromatographic system used provided good separation of the compound without interfering peaks from endogenous substance. The method is proved to be convenient, rapid, accurate and specific and has been successfully applied to pharmacokinetic study in rats.3The pharmacokinetics study of TAHP in ratsTotally30Sprague-Dawley rats equally were divided into five groups in random. The dosages of the four oral groups were set at50mg·kg-1,100mg·kg-1,200mg·kg-1for TAHP, and200mg/kg for hesperetin. The dosages of iv group was set at20mg·kg-1for TAHP. All blood samples were collected at different time after dosing. All collected blood were centrifuged to obtain plasma and the concentration of drug in plasma were determined by HPLC method described as above, then calculated corresponding pharmacokinetic parameters based on the time process of blood drug concentration. The main pharmacokinetic parameters(25,50,100mg·kg-1) were Tmax(h):1.30±1.13,1.80±1.30,3.17±0.41,0.33±0.10,0; Cmax(mg·L-1):0.90±0.13,1.65±0.34,4.27±0.84,4.63±1.15,13.25±1.82; AUQ(0-t)-mg·h·L-1):7.57±1.51,17.84±1.81,60.86±21.1754.23±14.10,23.97±4.90. The blood plasma cot curve of the active metabolite of TAHP conformed to two compartments model of the first order absorption. Compared with hesperetin of the same dosage, the half-life period and Tmax of TAHP was delayed, which would improve its short half-life period and quick elimination after per os. Comparing with low bioavailability of hesperidin, TAHP exhibited more effective anti-rheumatic activity than its parent compound hesperidin. |
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