Effect of tripterine on the pharmacokinetics of cyclosporine A and its mechanism in rats.

Tripterine is a key active component in Tripterygium wilfordii polyglycosides tablets. Cyclosporine A (CsA) is an immunosuppressive drug that is widely used in organ transplantation. The combined use of Tripterygium wilfordii and CsA can reportedly enhance the immunosuppressive effects of Cyclosporine whilst reducing its toxicity. Therefore, in the present study, a detection method for CsA concentration in rat blood samples was developed using liquid chromatography-mass spectrometry (MS)/MS. Reverse transcription-quantitative (RT-q) PCR and western blotting (WB) were used to examine the impact of tripterine on the expression of a variety of drug-metabolizing enzymes, drug transporters and nuclear receptors. Compared with that in the control group, the maximum concentration (C(max)) of CsA was found to be reduced across all tripterine dosage groups, where the area under the curve was significantly decreased in the 18 and 54 mg/kg groups. PCR and WB results indicated that tripterine inhibited the expression of cytochrome P450 (CYP) 3A1, CYP3A2, uridine diphosphate glucuronosyltransferase 1A1, organic anion-transporting polypeptide 1B2, p-glycoprotein 1, multidrug resistance-associated protein 2 (MRP2), breast cancer resistance protein, bile salt export pump (BSEP) and Na(+)-taurocholate co-transporting polypeptide (NTCP). These results suggest that tripterine's inhibition of NTCP, BSEP and MRP2 in the liver may disrupt bile acid circulation. Additionally, tripterine's activation of farnesoid X receptor in the intestine may limit bile acid synthesis, resulting in reduced CsA uptake into the bloodstream and inhibiting its enterohepatic circulation, ultimately leading to a decrease in CsA blood concentration. In addition, the combination of Tripterygium wilfordii and CsA have the prospect of joint clinical application. The present study demonstrated the inhibitory effect of tripterine on the pharmacokinetics of CsA, which could be of significance for the combined use of these two drugs.