In vitro and In vivo Synergistic Interactions of the Flavonoid Rutin with Paracetamol and with Non-Steroidal Anti-Inflammatory Drugs

The combination of drugs with different mechanisms of action could be more effective due to an enhanced synergistic activity. The pharmacological interactions between rutin and paracetamol, and rutin and non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen, ketorolac, and diclofenac were investigated using in vitro and in vivo assays.Individual and drug combination response curves of rutin-NSAIDs, and rutin-paracetamol (each at 0.001-0.1 mmol for in vitro studies and ranging from 1.25-100 mg/kg p.o. for in vivo studies) were evaluated in RAW 264.7 macrophages [inhibition of nitric oxide (NO) using the Griess reagent] and Balb/c mice (acetic acid-induced writhing test). An isobolographic analysis was used to assess the type of interaction between rutin and NSAIDs and rutin-paracetamol in a proportion of 1:1.Rutin alone and in combination with paracetamol and NSAIDs decreased NO production and the number of writhings in a concentration/dose-dependent manner. The isobolograms showed that all in vitro combinations of rutin-NSAIDs and rutin-paracetamol exerted synergistic effects. The combination rutin-diclofenac showed an interaction index of 0.17. In the in vivo assay, the combinations of rutin-diclofenac (interaction index = 0.195) and rutin-ketorolac (interaction index = 0.408) displayed synergistic effects, and the combination rutin-paracetamol exhibited additive effects.Rutin produces synergistic effects with paracetamol and NSAIDs in in vitro and in vivo assays.