title: Herb-drug interactions between Scutellariae Radix and mefenamic acid: Simultaneous investigation of pharmacokinetics, anti-inflammatory effect and gastric damage in rats.
abstract: BACKGROUND
  Scutellariae 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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  Minimal 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).
  
  
  CONCLUSIONS
  Co-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.
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: Sophia Yui Kau
authors.initials: SY
authors.lastname: Fong
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: Yin Cheong
authors.initials: YC
authors.lastname: Wong
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: Chen
authors.initials: C
authors.lastname: Xie
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong. Electronic address: joanzuo@cuhk.edu.hk.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D019540:Area Under Curve; D002460:Cell Line; D002853:Chromatography, Liquid; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D041743:Herb-Drug Interactions; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008528:Mefenamic Acid / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D031364:Scutellaria baicalensis; D053719:Tandem Mass Spectrometry
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D010936:Plant Extracts; C499814:Scutellaria baicalensis extract; D008528:Mefenamic Acid
keywords: Baicalein (PubChem CID: 5281605); Baicalin (PubChem CID: 64982), Wogonoside (PubChem CID: 3084961); Herb–drug interaction; Lipopolysaccharide (PubChem CID: 11970143); Mefenamic acid (PubChem CID: 4044); NSAIDs; Oroxylin A (PubChem CID: 5320315); Oroxyloside (PubChem CID: 44567248); Pharmacodynamics; Pharmacokinetics; Prostaglandin E(2) (PubChem CID: 5280360); Scutellariae Radix; Traditional Chinese medicine; Wogonin (PubChem CID: 5281703); Wogonoside (PubChem CID: 3084961)