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

AIM/BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Rutin produces synergistic effects with paracetamol and NSAIDs in in vitro and in vivo assays.