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. 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. 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. 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.

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 C_max (T_max) and reduced maximum concentration (C_max) 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 (t_1/2) and apparent volume of distribution (V_d), 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.