Pharmacovigilance of Herb-Drug Interactions: A Pharmacokinetic Study on the Combined Administration of Tripterygium Glycosides Tablets and Leflunomide Tablets in Rats by LC-MS/MS

A popular and widely used combination therapy of leflunomide (LEF) and Tripterygium glycosides tablets (TGT(S)) has become a valuable clinical tool in China for the treatment of rheumatoid arthritis. This regimen has not been evaluated either in terms of interaction or toxicity, even given the rising concerns about LEF's prolonged elimination half-life and TGT's narrow therapeutic index, in addition to the current trend of using high doses of LEF. Thus, this study determines the potential adverse drug reactions between these two medicines. Reliable validated LC-MS/MS methods were used for the determination of teriflunomide (TER, the only active metabolite of LEF), and the main components of TGT: wilforlide A, wilforgine, wilfortrine, wilfordine, and wilforine. The results obtained from this investigation, as paralleled with the control groups, revealed that the C-max and AUC(0-t) of TER were significantly decreased with separate co-administration, as the C-max and AUC(0-t) were 30.17 +/- 1.55 mu g/mL and 24.47 +/- 2.50 mu g/mL, 374.55 +/- 15.54 mu g h/mL and 336.94 +/- 21.19 mu g h/mL, respectively (p < 0.05). Meanwhile, the pharmacokinetic profiles of the main components of TGT have also been affected by separate co-administration in rats. Therefore, herb-drug interactions between LEF and TGT have been proven.