Abstract
Fructus polygoni orientalis (FPO) is widely used in clinical practice in China, especially in treatment of liver diseases including viral hepatitis, liver fibrosis, and liver cirrhosis. However, its pharmacokinetic (PK) alterations in liver fibrotic rats have rarely been reported. To study whether taxifolin, one of the main flavonoids in FPO can be absorbed into blood after oral administration of FPO extract and to compare the differences in pharmacokinetic parameters of taxifolin to normal and liver fibrotic rats induced by porcine serum (PS), a UPLC-MS/MS method was developed and validated for determination of taxifolin in rat plasma using puerarin as the internal standard (IS). All validation parameters met the acceptance criteria according to regulatory guidelines. The results indicated that after treatment of rats with PS alone for 12 weeks, the liver fibrotic model group was built successfully. The taxifolin can be absorbed into the blood after oral administration of the FPO extract. The Cmax of taxifolin was 1940 ± 502.2 ng/mL and 2648 ± 208.5 ng/mL (p < 0.05), the AUC0∼t of taxifolin was 4949.7 ± 764.89 h·ng/mL and 6679.9 ± 734.26 h·ng/mL (p < 0.05), the AUC0∼∞ of taxifolin was 5049.4 ± 760.7 and 7095.2 ± 962.3 h·ng/mL (p < 0.05), and the mean residence time (MRT) of taxifolin was 2.46 ± 0.412 h and 3.17 ± 0.039 h (p < 0.05) in the normal and fibrotic model groups, respectively. These results confirmed that the pharmacokinetic parameters of taxifolin are altered in liver fibrosis, manifested as Cmax, AUC0∼t, AUC0∼∞, and the mean residence time (MRT). It suggested that it is essential to consider the characteristics of pharmacokinetics after oral administration of FPO in liver disease patients.
Highlights
Liver fibrosis is a common pathological stage in chronic liver injury caused by various factors that leads to the accumulation of extracellular matrix (ECM) and formation of fibrous scars [1,2,3].Disruption of the liver structure by fibrous scars can result in the loss of hepatocyte cells and deregulation of normal liver functions and can develop into cirrhosis and liver failure [4, 5]
Mass chromatograms of taxifolin and IS obtained by extraction of blank rat plasma, blank plasma spiked with taxifolin and IS, and actual unknown plasma samples obtained in rats after oral administration of FPO extract are shown in Figure 2. e chromatographic run time for the extracted plasma samples was 5.0 min. e retention times for taxifolin and IS were 1.60 and 1.51 min, respectively. e chromatograms showed baseline separation of taxifolin and the IS without any interference from endogenous plasma components
Extraction Recovery and Matrix Effect. e matrix effects were expressed as the mean of the peak-area ratios of the blank plasma samples spiked with taxifolin after protein precipitation divided by the injected working solution with taxifolin at the same Quality control (QC) concentration
Summary
Liver fibrosis is a common pathological stage in chronic liver injury caused by various factors that leads to the accumulation of extracellular matrix (ECM) and formation of fibrous scars [1,2,3].Disruption of the liver structure by fibrous scars can result in the loss of hepatocyte cells and deregulation of normal liver functions and can develop into cirrhosis and liver failure [4, 5]. Liver fibrosis is a common pathological stage in chronic liver injury caused by various factors that leads to the accumulation of extracellular matrix (ECM) and formation of fibrous scars [1,2,3]. Animal experiments and clinical studies have shown that liver fibrosis, even early cirrhosis, is reversible [6, 7]. As a traditional Chinese medicinal herb, FPO is the dried and mature fruit of Polygonum orientale L. It has been used in China for the treatment of various liver diseases such as hepatitis, liver fibrosis, and cirrhosis [12].
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