The Cytochrome P450-Mediated Metabolism Alternation of Four Effective Lignans From Schisandra chinensis in Carbon Tetrachloride-Intoxicated Rats and Patients With Advanced Hepatocellular Carcinoma

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.

Caffeine-Containing, Adaptogenic-Rich Drink Modulates the Effects of Caffeine on Mental Performance and Cognitive Parameters: A Double-Blinded, Placebo-Controlled, Randomized Trial

“…For example, Ho et al [ 80 ] reported potent inhibition of CYP1A2 by crampbark ( Virburnum opolus ) using a microplate-based assay of cDNA expressed CYP isoforms. Similarly, Schisandra chinensis has also been found to variably modify CYP isoforms [ 81 ]. Finally, Sheriffdeen et al [ 82 ] observed other traditional herbal medicines (not those found in e+ shot) inhibited CYP1A2-mediated metabolism of caffeine humans upon acute consumption of these herbs, most likely through competitive and/or non-competitive enzymatic inhibition.…”

Elucidation of the Differences in Cinobufotalin’s Pharmacokinetics Between Normal and Diethylnitrosamine-Injured Rats: The Role of P-Glycoprotein

“…In addition, it has been reported that hydroxylation and dehydrogenation mediated by Cytochrome P450 (CYP450) enzymes, especially CYP3A4, were the major metabolic pathways of cinobufotalin in vitro and in vivo (Han et al, 2016). Hence the activity reduction of multiple CYP450 isoenzymes in the HCC rat models (Peng and Ding, 2015; Wu R. et al, 2018) should lead to slower clearance rate of cinobufotalin, showing lower k 10 . Because that k 10 is the elimination rate constant that depends on metabolism and excretion of the compounds or drugs.…”

Potential for pharmacokinetic interactions between Schisandra sphenanthera and bosutinib, but not imatinib: in vitro metabolism study combined with a physiologically‐based pharmacokinetic modelling approach

“…The intrinsic clearance ( CL int ) of schisandrin A was obtained from re‐analysis of its depletion in HLM, while contribution of CYP3A enzymes ( f m,CYP3A = 0.76) was estimated from the percent of inhibition by ketoconazole 11 . CL int of schisantherin A 9 and schisandrol B 12 were also specified based on their metabolic pathways 11 .…”

“… g Total CL int value was extracted from Zhang et al 9 and f m , CYP3A4 was estimated based on the extent of inhibition by ketoconazole 11 …”

“… h Total CL int was determined from substrate depletion in human liver microsomes and f m , CYP3A4 was based on percent of inhibition by ketoconazole 11 …”