| Trans ?-viniferin (Rs-1) was found in grapevine (Vitis vinifera L.), and many studies have demonstrated that Rs-1 has lots of pharmacological abilities, such as anti-inflammation, antimicrobial effect, antioxidation, cardioprotection and antidiabetes. Penta-O-acetyl-?-viniferin (AcRs-1) was synthesized by acetylating five hydroxyl groups of ?-viniferin. It has higher hydrophobicity than the parent molecule, which might increase the ability to cross the cellular membrane. In this study, we investigate and compare the pharmacokinetics of Rs-1 and AcRs-1 in rats following a single oral administration or intravenous injection.In the present study, a sensitive and accurate LC-MS/MS method was developed and validated for the determination of Rs-1 and AcRs-1 in rat plasma, urine and feces. A liquid-liquid extraction (LLE) method was applied to extract the analyte from biological samples (plasma, urine and feces), and the extraction solvent was ethyl acetate or diethyl ether. The supernate was evaporated to dryness under nitrogen at 40?. Then the residue was reconstituted in methanol or acetonitrile. Chromatographic separation was achieved on a shim-pack XR-ODS column (3×75 mm,2.2?m) using gradient mobile phase with acetonitrile (0.1% formic acid)-water (0.1% formic acid). hesperetin was used as an internal standard (IS-1) of Rs-1, and MS/MS detection was performed by negative ion electrospray ionization using MRM transitions at m/z 453.2?411.2 for Rs-1 and m/z 301.1?163.9 for IS-1. Deoxyschizandrin was used as an internal standard (IS-2) of AcRs-1, and MS/MS detection was performed by positive ion electrospray ionization using MRM transitions at m/z 665.1?581.2 for Rs-1 and m/z 417.2?316.2 for IS-2.The method of Rs-1 was sensitive with a lower limit of quantification of 1.42 ng/mL and linear over the range of 1.42?2172 ng/mL in all matrices, r> 0.99. The intra-day and inter-day precision (RSD,%) values were both ?3.7%, the accuracy (RE,%) were in the range of -4.9 to 5.6%. The extraction recovery was 70.7%?90.4%, RSD<9.3%. The matrix effect was 85.8%?100.4%, RSD<4.7%.The method of Rs-1 was sensitive with a lower limit of quantification of 1.33 ng/mL and linear over the range of 1.33?2022 ng/mL in all matrices, r>0.99. The intra-day and inter-day precision (RSD,%) values were both ?4.3%, the accuracy (RE,%) were in the range of -3.6?2.8%%. The extraction recovery was 82.2%?98.2%%. The matrix effect was 90.1%?100.7%?The reliable method was subsequently applied to the assessment of the pharmacokinetics, bioavailability, metabolism and excretion of AcRs-1 and Rs-1 in healthy rats following a single oral administration (155?mol/ml) or intravenous injection (3 umol/ml). The pharmacokinetic parameters were evaluated by non-compartmental model using DAS Software. The results were as follows:After intravenous injection of Rs-1 or AcRs-1, a small amount of Rs-1 glucuronide and sulfate conjugates were detected. After intravenous injection of Rs-1, Rs-1 was the main compound in the plasma. While owe to the phosphatases, AcRs-1 in plasma can easily lose the acetyls. There were some compounds with three acetyls, two acetyls, one acetyls within and Rs-11 h after intravenous injection of AcRs-1, and the t1/2 of the total Rs-1s (Rs-1 and Rs-1 with diffrent amount of acetyls) has been prolonged and the Area under the curve (AUC) has been enhanced compare to intravenous injection of Rs-1.After oral administration Rs-1, it was metabolized rapidly to Rs-1 glucuronide and sulfate conjugates. The absolute oral bioavailability of Rs-1 was 2.3%, and the total absorption was rose to 31.5% in addition to its glucuronide and sulfate metabolites. Only 0.09% of the gavage dose, including Rs-1 and it metabolites, were excreted through urine; while 60.3% were through feces in unchanged form. After oral administration of AcRs-1, there was little AcRs-1 or any other form of metabolites in plasma and urine, while 94.8% was recovered in feces (contain Rs-1 and Rs-1 with diffrent amount of acetyls) and mainly remained unchanged, which implied that AcRs-1 was barely absorbed (78.3%).This study compared pharmacokinetics, bioavailability, metabolism and excretion of AcRs-1 and Rs-1. The results showed that AcRs-1 was barely absorbed after oral administration. Maybe the more poor solubility and high molecular weight makes AcRs-1 was more difficult to absorb. Acetylation of Rs-1 was not a good way to improve the bioavailability. The developed method and the pharmacokinetic data can provide a basis for further studies. |
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