Effects of Shaoyao-Gancao-Fuzi Decoction on the Pharmacokinetics of CYP3A4-Mediated Tofacitinib in Rats

Abstract

Background: The combination of traditional Chinese medicine and western medicine is commonly accepted in clinics in China. Shaoyao-Gancao-Fuzi decoction (SGFD) has been extensively used to dispel wind, eliminate dampness and treat paralysis. Tofacitinib is approved for the treatment of rheumatoid arthritis. SGFD and tofacitinib could be used together for the treatment of rheumatoid arthritis.Methods: A cocktail approach was employed to assess the effects of SGFD on the activities of CYP450s. After pretreatment for 2 weeks with SGFD, a cocktail solution was given to rats 24 h after the last dose of saline or SGFD. Additionally, the pharmacokinetic profiles of oral administration of tofacitinib in rats, with or without SGFD pre-treatment were investigated.Results: The results showed that SGFD could induce the activity of CYP1A2 and inhibit the activity of CYP3A4. Furthermore, SGFD could significantly affect the pharmacokinetics of tofacitinib. Compared with control group, the AUC0-∞ of tofacitinib was increased from 13669.53 ± 4986.83 to 28706.69 ± 9563.13 ng/mL*h (p < 0.01), and the Cmax was increased from 8359.66 ± 1512.22 to 11332.51 ± 2791.90 ng/mL (p < 0.05).Conclusions: The system exposure of tofacitinib was increased by SGFD. The mechanism might be through inhibiting the activity of CYP3A4 and reducing the metabolism of tofacitinib in rats. The study will provide better guidance for the safe clinical use of SGFD and tofacitinib.