Ethnopharmacological relevance: Cooked rhubarb and wine processed rhubarb are the processed rhubarbs of raw rhizomes from Rheum palmatum L.; Rheum tanguticum Maxim. ex Balf. or Rheum officinale Baill. They are clinically used in traditional Chinese medicine to compose anti-diabetic formulas and remove pathogenic heat or toxin from the body. Aim of the study: To elucidate potential influences processed rhubarbs might have on the activities of four cytochrome P450 (CYP) isozyme in rats (CYP1A2, CYP2C6, CYP2E1, and CYP3A1) and on the pharmacokinetics of saxagliptin. Materials and methods: Relative activity estimation of four isozymes or influence on saxagliptin was carried out by comparing plasma pharmacokinetics of four respective substrates (theophylline for CYP1A2, tolbutamide for CYP2C6, chlorzoxazone for CYP2E1, and dapsone for CYP3A1) or saxagliptin between control and processed rhubarbs pretreated groups. Plasma concentrations of substrates and saxagliptin were quantified using UPLC-UV and UPLC-MS/MS methods, respectively. Results: Wine processed rhubarb induced CYP1A2 activity; both the processed rhubarbs inhibited the CYP2C6 activity and induced CYP2E1; cooked rhubarb induced CYP3A1 activity. Both the processed rhubarbs reduced the absorbance and bioavailability, but increased the clearance of saxagliptin. Conclusions: Processed rhubarbs can either induce or inhibit activities of CYP1A2, CYP2C6, CYP2E1, and CYP3A1, and modify the metabolism of saxagliptin. The results indicated that drug co-Administrated with processed rhubarbs may need dose adjustment. © 2012 Elsevier Ireland Ltd.