ABSTRACT
BACKGROUND: Tripterygium wilfordii (TW) is widely employed to treat rheumatoid arthritis and autoimmune disorders clinically, which, however, accompany with disturbing hepatotoxicity and nephrotoxicity. The previous research showed that Panax notoginseng (PN) compatibly and significantly reduces the TW-induced hepatotoxicity. OBJECTIVE: To explore the underlying mechanism, the present study was designed to reveal the influence of PN on the intestinal absorption process of TW-derived active components in rat. MATERIALS AND METHODS: An in situ single-pass intestinal perfusion technique was established and preformed to obtain the perfusate samples of triptolide (TP), tripterine (TE), TW extract, and TW-PN extract. A rapid and sensitive ultra-performance liquid-chromatography tandem mass spectrometry method was subsequently developed and validated to determine the concentrations of TP and TE in the perfusate samples. Then, the absorption parameters, effective permeability, absorption rate constant, and percentage of 10 cm intestinal absorption were calculated strictly. RESULTS: The final data indicated that both TP and TE have no special absorption site in the intestine and are primarily absorbed in a passive manner. Otherwise, the absorption of TP was decreased from compatibility of PN, but the absorption of TE was enhanced. CONCLUSION: The absorption reduction of TP and absorption elevation of TE from TW initiated by the combination of PN are contributed to attenuate the toxicity and reinforce the therapeutic efficacy of TW. It is practically reasonable of usage of TW compatibility with PN clinically. SUMMARY: Panax notoginseng (PN) regulated the absorption process of Tripterygium wilfordii (TW) in intestineBoth triptolide (TP) and tripterine (TE), two typical components of TW, have no special absorption site in the intestine and are primarily absorbed in a passive mannerPN decreased the absorption of TP and enhanced the absorption of TE in the intestine. Abbreviations used: 10 cm% ABS: percentage of 10 cm intestinal absorption, DMARDs: Disease-modifying antirheumatic drugs, GU: Glycyrrhiza uralensis, Ka: Absorption rate constant, NSAIDs: Nonsteroidal anti-inflammatory drugs, Peff: Effective permeability, PN: Panax notoginseng, QC: Quality control, RA: Rheumatoid arthritis, RG: Rehmannia glutinosa, SPIP: Single-pass intestinal perfusion, TE: Tripterine, TP: Triptolide, TW: Tripterygium wilfordii, UPLC-MS/MS: Ultra-performance liquid-chromatography tandem mass spectrometry.
ABSTRACT
BACKGROUND: Compatibility with Panax notoginseng (PN) reduced the plasma concentration of triptolide and delayed the Tmax of Tripterygium wilfordii (TW), the sovereign medicine of Qing-Luo Tong-Bi decoction, which hinted the absorption process of triptolide might be involved in decreasing the toxicity in liver and kidney. METHODS: The absorption of triptolide, triptonide, wilforlide and tripterine from monomer, TW, TW-PN, TW-Caulis Sinomenii (TW-CS) and Qing-Luo Tong-Bi were analyzed in duodenum, jejunum, ileum and colon of rat via single-pass intestinal perfusion model. An UPLC-MS/MS analysis method was developed to determine the concentration of triptolide, triptonide, wilforlide and tripterine in the inlet and outlet. Then Peff, 10 cm%ABS and Ka were calculated based on the perfusate flux, perfusate volume and candidate chemicals concentration. RESULTS: The absorption of triptolide, triptonide, wilforlide and tripterine in duodenum, jejunum, ileum and colon was independent of concentration within range of 3-9 µg/mL. The target compounds, triptolide, triptonide, wilforlide and tripterine from the TW extract, showed higher absorption extent and rate than those administrated alone, and compared with the absorption situation of the chemicals of TW extract, the absorption of triptolide, triptonide and wilforlide of the extract of TW-PN, TW-CS and Qing-Luo Tong-Bi were decreased in these intestinal segments. However, PN-promoted tripterine absorption was observed in the intestine. CONCLUSIONS: Modulation of absorption of chemicals in TW by subsidiary herbs may be responsible for reinforcing the actions and neutralizing the adverse effects through compatibility in the formula of Qing-Luo Tong-Bi. PN inhibits the absorption of triptolide of TW and promote the absorption of tripterine.
ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: The key problem with toxic Chinese herbs in clinical applications is how to find the most effective method to reduce toxicity. This study focuses on discussing the mechanism of decreased hepatotoxicity by the usage compatibility of two commonly used traditional Chinese drugs that are used clinically: Tripterygium wilfordii Hook. f. (TW) and Panax notoginseng (Burkill) F.H. Chen (PN). Additionally, based on the results from using metabonomics technology, the usage compatibility with these two herbs that was originated from clinical experience is the first to clarify the rationality of the drug combination. MATERIALS AND METHODS: Through a fast and effective HPLC method, plasma concentration-time profiles and triptolide distribution characteristics in liver, heart, spleen, lung and kidney tissues were simultaneously determined in rats after oral administration of the aqueous extract of TW and TW-PN. The reduced hepatotoxicity data of the usage compatibility with TW and PN were also investigated, and then a UHPLC-QTOF/MS method was developed and validated for the explanation of the reduced hepatotoxicity mechanism. RESULTS: It was indicated that nine endogenous metabolites might be potential biomarkers for hepatotoxicity induced by TW. In addition, the plasma concentration-time profiles and the distribution characteristics of TP in rats were changed after oral administration of the aqueous extract of TW-PN, and simultaneously, the hepatotoxicity was obviously decreased. CONCLUSIONS: The results indicated that usage compatibility with TW and PN was reasonable in clinical use. To the best of our knowledge, this is the first report to describe the mechanism of reducing hepatotoxicity with the combined use of TW and PN from clinical experience.
