Abstract
It is highly valuable to study the pharmacokinetics of herbal components under the pathological condition of liver dysfunction for safe and rational use of herbal medicines. In this study, the pharmacokinetic profiles of four effective lignans from Schisandra chinensis (SC), schisandrin, schisantherin A, deoxyshisandrin and γ-schisandrin, were investigated in carbon tetrachloride (CCl4)-intoxicated rats. The metabolism of the four lignans was also studied using microsomes from patients with advanced hepatocellular carcinoma. In situ intestinal and hepatic perfusions were conducted to clarify the contributions from impairments of gut and liver on the pharmacokinetics of the four schisandra lignans in CCl4-intoxicated rats. The metabolism in rat and human liver microsomes and transport in Caco-2 monolayer cell model were studied to reveal the key factors for the in vivo disposition of the four lignans. When SC alcoholic extract was orally administrated to CCl4-intoxicated rat for a short term (4 days), the pharmacokinetics of four active SC lignans was significantly changed while its hepatotherapeutic effect was not obviously observed. The plasma concentrations of the four schisandra lignans were dramatically elevated compared with the control. The Cmax, AUC and MRT were all increased or prolonged significantly while parameter CLz/F was obviously reduced in rat pretreated with CCl4. In hepatic perfusion study and liver microsomes incubation, it was found that the hepatic metabolism of the four lignans was markedly decreased mainly due to the activity reduction of multiple CYP450 isoenzymes involved the metabolism, which, eventually, might lead to the alternation of their pharmacokinetic profiles in CCl4-intoxicated rats or patients with advanced hepatocellular carcinoma. The pharmacokinetic studies of SC components in pathological situation of liver dysfunction are expected to provide useful data for rational and safe application of SC preparations in clinic or further pharmacological and toxicological research.
Highlights
Investigations revealed that the use of herbal medicines, usually as the complementary and alternative treatment, increased dramatically and became popular around the world (RamosRemus and Raut, 2008; Harris et al, 2012; Putthapiban et al, 2017)
Serum alanine transaminase (ALT) and aspartate transaminase (AST), and blood urea nitrogen (BUN) was increased by 40, 720, 30, and 30% in acute liver injury (ALI) rat intoxicated with CCl4, while the content of liver microsomal cytochrome P450 (CYP450) enzyme was decreased by 56% compared with control rats
It was found that the 4day administration of Schisandra chinensis (SC) alcoholic extract (1.5 g/kg/day) did not show positive effect on the liver dysfunction in ALI rats indicated by elevated serum ALT and AST or decreased CYP450 content
Summary
Investigations revealed that the use of herbal medicines, usually as the complementary and alternative treatment, increased dramatically and became popular around the world (RamosRemus and Raut, 2008; Harris et al, 2012; Putthapiban et al, 2017). The pharmacokinetic profiles of drugs could be altered by the dysfunctions of liver in pathological conditions, which exerts a negative effect on drug safety and therapy (Tamura et al, 2004). It is highly valuable to conduct the pharmacokinetic study of herbal components under the pathological condition of liver dysfunction, which could provide reliable and referential data for safe and rational clinical application of herbal drugs (McLean and Morgan, 1991; Yokogawa et al, 2004). The pharmacokinetics of the SC lignans was correlated well with CYP3A, ALT and AST (Xie et al, 2010) Based on these former results, the pharmacokinetics of SC ingredients under conditions of liver dysfunctions should be further studied concerning that SC ingredients were often applied for treatment of various liver diseases
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