Herb-drug Interactions between Scutellariae Radix and Non-steroidal Anti-inflammatory Drugs: Pharmacokinetic and Pharmacodynamic Impact.

摘要

Purpose: Scutellariae Radix (RS) and non-steroidal anti-inflammatory drugs (NSAIDs), being Chinese and Western medicines respectively, have a lot in common. Both of them are substrates of phase II metabolic enzymes, possess antiinflammatory activities, and are clinically indicated for inflammatory diseases. While both drugs share the same indication, the opportunity of patients co-administering RS and NSAIDs is considerably high, yet study on their potential herb-drug interaction is limited. The current study aims to 1) screen for the most potent NSAID that alter the hepatic metabolism of RS; and 2) comprehensively evaluate the pharmacokinetic and pharmacodynamic interactions between RS and the selected NSAID.;Methods: Literature review followed by in vitro screening using liver microsomes/cytosols was employed to identify the most potent NSAIDs that could inhibit the metabolism of RS bioactive components. Pharmacokinetic interactions between the selected NSAID and a standardized RS extract were mechanistically evaluated at different sites, including liver (using rat liver microsomes/cytosols), intestine (using Caco-2 cell monolayer model and rat in situ single-pass intestinal perfusion model), and plasma protein (using rat plasma protein binding assay). Pharmacodynamic interactions were evaluated at in vitro, ex vivo, and in vivo levels, employing lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells and LPS-induced systemic inflammation rat model. Furthermore, interactions between the selected NSAID and RS extract on the pharmacokinetics, anti-inflammatory effect and stomach ulcer adverse effect were simultaneously monitored in rats receiving 5-day multiple oral doses according to clinical settings.;Results: Fourteen NSAIDs were included in the initial in vitro screening. Diflunisal, mefenamic acid (MEF) and niflumic acid were the three most potent inhibitors on the hepatic glucuronidation and sulfation of the bioactive components of RS. Taken clinical popularity into consideration, MEF was selected for further mechanistic and in vivo interaction studies with a standardized RS extract. In order to simultaneously quantify MEF and the six bioactive components of RS, including baicalein, baicalin, wogonin, wogonoside, oroxylin A and oroxyloside, in both in vitro and biological samples, a sensitive LC/MS/MS assay method was developed and fully validated. The major metabolites of MEF, including glucuronidated and hydroxyl metabolites, were identified by the developed assay. From the pharmacokinetic-based mechanistic studies, RS extract dose-dependently inhibited the hydroxylation, glucuronidation and plasma protein binding of MEF, while it had minimal impact on the intestinal disposition of MEF. On the other hand, MEF inhibited the hepatic and intestinal glucuronidation and sulfation of the bioactive components of RS leading to the increased intestinal absorption of wogonin and oroxylin A. Pharmacodynamically, RS extract and MEF interacted via the cyclooxygenase-2 (COX-2) pathway. The combination of RS extract and MEF produced a significantly potentiated and time-dependent inhibition on the production of prostaglandin E2 (PGE2) in vitro and in vivo. From the simultaneous pharmacokinetic and pharmacodynamic interaction study in vivo, oral co-administration of RS extract and MEF significantly potentiated the PGE2-inhibitory effect and prolonged the inhibitory effect on COX-2 gene expression. Meanwhile, RS extract significantly alleviated the MEF-induced stomach ulcer. Nevertheless, minimal pharmacokinetic interactions were observed.;Conclusion: Safe combinational use of RS extract and MEF was demonstrated. With potential benefits in enhancing the therapeutic effect (anti-inflammatory effect) while alleviating the adverse effect (stomach ulcer), RS extract was demonstrated to be a promising candidate as combination therapy with MEF to treat inflammatory diseases.