Herb–drug interactions between Scutellariae Radix and mefenamic acid: Simultaneous investigation of pharmacokinetics, anti-inflammatory effect and gastric damage in rats

Abstract

Ethnopharmacological relevanceScutellariae Radix (SR), the dried root of Scutellariae baicalensis Georgi, has a lot in common with non-steroidal anti-inflammatory drugs (NSAIDs). Their similarities in therapeutic action (anti-inflammation) and metabolic pathways (phase II metabolisms) may lead to co-administration by patients with the potential of pharmacokinetic and/or pharmacodynamic interactions. The current study aims to investigate the potential interactions between SR and an NSAID, mefenamic acid (MEF), on the overall pharmacokinetic dispositions, anti-inflammatory effects and adverse effects in rats. Materials and methodsThe current study simultaneously monitored the pharmacokinetic and pharmacodynamic interactions in a single animal. Four groups of Sprague-Dawley rats (n=7 each) received oral doses of a standardized SR extract (300mg/kg, twice daily), MEF (40mg/kg, daily), combination of SR extract and MEF, and vehicle control, respectively, for 5 days. On Day 5, blood samples were collected after first dose over 24h for the determination of (1) plasma concentrations of SR bioactive components, MEF and its metabolites by LC-MS/MS, and (2) prostaglandin E2 (PGE2) production and cyclooxygenase-2 (COX-2) gene expression by ex vivo analyses using LPS-stimulated RAW264.7 macrophage cells, ELISA and real time-PCR. After the rats were sacrificed, stomachs were isolated to assess their gross mucosal damage. Statistical comparisons were conducted using ANOVA and t-test. ResultsMinimal pharmacokinetic interaction between SR extract and MEF was observed. Co-administration of SR extract and MEF did not significantly alter the plasma concentration–time profile or the pharmacokinetic parameters such as Cmax, AUC0→24, Tmax or clearance. Pharmacodynamic interaction via the COX-2 pathway was observed. The PGE2 level in LPS-stimulated RAW264.7 cells treated with plasma collected from control group over the 24h sampling (AUC0→24[PGE2]) was 191981±8789pg/mlhr, which was significantly reduced to 174,780±6531 and 46,225±1915pg/mlhr by plasma collected from rats administered with SR extract and MEF, respectively. Co-administration of SR extract and MEF further potentiated the PGE2 inhibition, with an AUC0→24[PGE2] of 37013±2354pg/mlhr (p<0.05, compared to SR or MEF group). By analyzing the COX-2 gene expression, SR extract significantly prolonged the COX-2 inhibitory effect of MEF over the 24h (p<0.05). Furthermore, the MEF-induced stomach ulcer after the 5-day treatment, as evidenced by the increased gross ulcer index and sum of lesion length (p<0.05, compared to control), could be alleviated by co-administration with SR extract (p<0.05). ConclusionsCo-administration of SR extract and MEF potentiated the anti-inflammatory effects, alleviated the MEF-induced stomach adverse effect while having minimal pharmacokinetic interactions. Our findings provide insight for combination therapy of SR extract and MEF against inflammatory diseases.