Compatibility with Panax notoginseng and Rehmannia glutinosa Alleviates the Hepatotoxicity and Nephrotoxicity of Tripterygium wilfordii via Modulating the Pharmacokinetics of Triptolide

Abstract

Tripterygium wilfordii (TW) and the representative active component triptolide show positive therapeutic effect on the autoimmune disorders and simultaneously ineluctable hepatotoxicity and nephrotoxicity. Combinational application of Panax notoginseng (PN) and Rehmannia glutinosa (RG) weakens the toxicity of TW according the clinical application of traditional Chinese medicine. This article was aimed at the mechanism of decreasing toxicity of TW by the combinational application of PN and RG. Biochemical and pathohistological analysis were utilized to assess the toxicity on liver and kidney in rats administrated with TW, TW-PN, TW-RG and TW-PN-RG for 3 and 7 days. Meanwhile, the pharmacokinetics profiling of triptolide and wilforlide A was determined based on the plasma concentration analyzed by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). TW-induced alkaline phosphatase (ALP), the marker for liver injury, was enhanced from 22.83 ± 1.29 to 40.73 ± 1.42 King’s unit/100 mL (p < 0.01) at day 7. TW-PN-RG decreased the serum ALP of TW-treated rats at 30.15 ± 1.27 King’s unit/100 mL (p < 0.01). For nephrotoxicity, TW pronouncedly elevated serum creatinine (SCr) in rats from 20.33 ± 1.77 to 49.82 ± 2.35 μmol/L (p < 0.01). However, rats treated with TW-PN-RG showed lower SCr at 30.48 ± 1.98 μmol/L (p < 0.01). Moreover, TW-PN-RG significantly decreased the TW-induced elevation of total bilirubin (T-BIL), alanine amino transferase (ALT), aspartate amino transferase (AST), blood urea nitrogen (Bun), and reversed the TW-resulted pathohistological characteristics of liver and kidney. The delayed time to reach Cmax (Tmax) and reduced maximum concentration (Cmax) and area under plasma concentration-time curve (AUC) of triptolide and wilforlide A were explored in rats with combinational formulas. Synergism of PN and RG obviously prolonged the half-life (t1/2) and apparent volume of distribution (Vd), but exerted no action on the clearance rate. The compatibility of TW, PN and RG influences intracorporal process of both triptolide and wilforlide A on the steps of absorption and tissue distribution contributing to less toxicity of TW on liver and kidney.

Adverse Events Associated With Treatment of Tripterygium wilfordii Hook F: A Quantitative Evidence Synthesis

“…A study (which included 428 trials) published in 2016 reported that the incidence of all grades of AEs caused by TwHF preparations was 26.7% [95% CI (24.8–28.8)]. The results of that systematic review were similar to our findings, but it included all types of TwHF preparations and 94% (402/428) of the included trials were from Chinese databases (Zhang et al, 2018). The use of all types of TwHF preparations might increase statistical heterogeneity, and literatures of low quality might lead to low quality of methodology.…”

“…Previous studies have shown that the AEs caused by TWP mainly include leukopenia, gastrointestinal reactions, menstrual disorders, and liver dysfunction (Zhang et al, 2016). Incidences of leukopenia and liver dysfunction have significantly increased in patients treated for immune system disease, and independent incidences of AEs caused by TwHF have been associated with various organ toxicities, such as intestinal toxicity, reproductive toxicity, hepatotoxicity, nephrotoxicity, hematotoxicity, and cutaneous toxicity (Liu et al, 2018; Zhang et al, 2018). This indicates that the therapeutic dose of TwHF is close to its toxic dose, resulting in unavoidable occurrence of AEs.…”

Literature Review of Traditional Chinese Medicine Herbs–Induced Liver Injury From an Oncological Perspective With RUCAM

“…Lists of herbs and concoctions that were hepatotoxic or hepatoprotective, their respective causality levels, and number of cases are compiled in Tables 1 to 5. 9,13-46…”

Mechanisms of Triptolide-Induced Hepatotoxicity and Protective Effect of Combined Use of Isoliquiritigenin: Possible Roles of Nrf2 and Hepatic Transporters

“…When prejaundill occurs. Clinical symptoms of TP-induced liver injuries include jaundice ( Xue et al, 2009 ), and Zhang et al (2018) found that tripterygium wilfordii significantly increased the total bilirubin in rat serum, which may be related to the changes in transporter expressions.…”