We investigated the involvement of drug transporters in the pharmacokinetics of rosmarinic acid in rats as well as the transporter-mediated drug interaction potential of rosmarinic acid in HEK293 cells overexpressing clinically important solute carrier transporters and also in rats. Intravenously injected rosmarinic acid showed bi-exponential decay and unchanged rosmarinic acid was mainly eliminated by urinary excretion, suggesting the involvement of transporters in its renal excretion. Rosmarinic acid showed organic anion transporter (OAT)1-mediated active transport with a K_m of 26.5 μM and a V_max of 69.0 pmol/min in HEK293 cells overexpressing OAT1, and the plasma concentrations of rosmarinic acid were increased by the co-injection of probenecid because of decreased renal excretion due to OAT1 inhibition. Rosmarinic acid inhibited the transport activities of OAT1, OAT3, organic anion transporting polypeptide (OATP)1B1, and OATP1B3 with IC₅₀ values of 60.6 μM, 1.52 μM, 74.8 μM, and 91.3 μM, respectively, and the inhibitory effect of rosmarinic acid on OAT3 transport activity caused an in vivo pharmacokinetic interaction with furosemide by inhibiting its renal excretion and by increasing its plasma concentration. In conclusion, OAT1 and OAT3 are the major transporters that may regulate the pharmacokinetic properties of rosmarinic acid and may cause herb-drug interactions with rosmarinic acid, although their clinical relevance awaits further evaluation.

We evaluated the bioavailability, liver distribution, and efficacy of silymarin-D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) solid dispersion (silymarin-SD) in rats with acetaminophen-induced hepatotoxicity (APAP) compared with silymarin alone. The solubility of silybin, the major and active component of silymarin, in the silymarin-SD group increased 23-fold compared with the silymarin group. The absorptive permeability of silybin increased by 4.6-fold and its efflux ratio decreased from 5.5 to 0.6 in the presence of TPGS. The results suggested that TPGS functioned as a solubilizing agent and permeation enhancer by inhibiting efflux pump. Thus, silybin concentrations in plasma and liver were increased in the silymarin-SD group and liver distribution increased 3.4-fold after repeated oral administration of silymarin-SD (20 mg/kg as silybin) for five consecutive days compared with that of silymarin alone (20 mg/kg as silybin). Based on higher liver silybin concentrations in the silymarin-SD group, the therapeutic effects of silymarin-SD in hepatotoxic rats were evaluated and compared with silymarin administration only. Elevated alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels were significantly decreased by silymarin-SD, silymarin, and TPGS treatments, but these decreases were much higher in silymarin-SD animals than in those treated with silymarin or TPGS. In conclusion, silymarin-SD (20 mg/kg as silybin, three times per day for 5 days) exhibited hepatoprotective properties toward hepatotoxic rats and these properties were superior to silymarin alone, which may be attributed to increased solubility, enhanced intestinal permeability, and increased liver distribution of the silymarin-SD formulation.

The present findings suggest that GPR35 functions as a migration inhibitory receptor, but CXCL17-stimulated migration of THP-1 cells is not dependent on GPR35.

We investigated the involvement of drug transporters in the pharmacokinetics of rosmarinic acid in rats as well as the transporter-mediated drug interaction potential of rosmarinic acid in HEK293 cells overexpressing clinically important solute carrier transporters and also in rats. Intravenously injected rosmarinic acid showed bi-exponential decay and unchanged rosmarinic acid was mainly eliminated by urinary excretion, suggesting the involvement of transporters in its renal excretion. Rosmarinic acid showed organic anion transporter (OAT)1-mediated active transport with a K_m of 26.5 μM and a V_max of 69.0 pmol/min in HEK293 cells overexpressing OAT1, and the plasma concentrations of rosmarinic acid were increased by the co-injection of probenecid because of decreased renal excretion due to OAT1 inhibition. Rosmarinic acid inhibited the transport activities of OAT1, OAT3, organic anion transporting polypeptide (OATP)1B1, and OATP1B3 with IC₅₀ values of 60.6 μM, 1.52 μM, 74.8 μM, and 91.3 μM, respectively, and the inhibitory effect of rosmarinic acid on OAT3 transport activity caused an in vivo pharmacokinetic interaction with furosemide by inhibiting its renal excretion and by increasing its plasma concentration. In conclusion, OAT1 and OAT3 are the major transporters that may regulate the pharmacokinetic properties of rosmarinic acid and may cause herb-drug interactions with rosmarinic acid, although their clinical relevance awaits further evaluation.

We evaluated the bioavailability, liver distribution, and efficacy of silymarin-D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) solid dispersion (silymarin-SD) in rats with acetaminophen-induced hepatotoxicity (APAP) compared with silymarin alone. The solubility of silybin, the major and active component of silymarin, in the silymarin-SD group increased 23-fold compared with the silymarin group. The absorptive permeability of silybin increased by 4.6-fold and its efflux ratio decreased from 5.5 to 0.6 in the presence of TPGS. The results suggested that TPGS functioned as a solubilizing agent and permeation enhancer by inhibiting efflux pump. Thus, silybin concentrations in plasma and liver were increased in the silymarin-SD group and liver distribution increased 3.4-fold after repeated oral administration of silymarin-SD (20 mg/kg as silybin) for five consecutive days compared with that of silymarin alone (20 mg/kg as silybin). Based on higher liver silybin concentrations in the silymarin-SD group, the therapeutic effects of silymarin-SD in hepatotoxic rats were evaluated and compared with silymarin administration only. Elevated alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels were significantly decreased by silymarin-SD, silymarin, and TPGS treatments, but these decreases were much higher in silymarin-SD animals than in those treated with silymarin or TPGS. In conclusion, silymarin-SD (20 mg/kg as silybin, three times per day for 5 days) exhibited hepatoprotective properties toward hepatotoxic rats and these properties were superior to silymarin alone, which may be attributed to increased solubility, enhanced intestinal permeability, and increased liver distribution of the silymarin-SD formulation.

The present findings suggest that GPR35 functions as a migration inhibitory receptor, but CXCL17-stimulated migration of THP-1 cells is not dependent on GPR35.

Clinical Research Information Service Identifier: KCT0004026.

Therapeutic effects of PD on the esophageal and gastric lesions were shown in RE induced rats dose-dependently. The PD pretreatment had significant antioxidant effects with regulation of histamine levels. This study provides useful information regarding the effectiveness of the drug for RE and further novel drug discovery using natural herbal products.

Background In Oriental countries, the root of Saussurea lappa is used to treat asthma, rheumatism, and other conditions. Extracts of Saussurea lappa were reported to alleviate house dust mite‐induced atopic‐like dermatitis in Nc/Nga mice, and sesquiterpene lactones were isolated. METHODS To elucidate whether elecampane camphor, a constuent of Saussurea lappa extract has beneficial effects on allergic asthma, anti‐asthma effects were studied using female Balb/c mice and rat RBL‐2H3 mast cells. Antigen‐induced degranulation was measured in vitro by measuring β‐hexosaminidase activity. A murine ovalbumin‐induced allergic asthma model was used to test the in vivo efficacy of the elecampane camphor. RESULTS Antigen‐induced degranulation was inhibited by the elecampane camphor. Sensitization and challenge of ovalbumin induced allergic asthma responses. Administration of elecampane camphor decreased numbers of inflammatory cells, especially eosinophils, and reduced the expression and secretion of Th2 cytokines, including IL‐4 and IL‐13, in lung tissues and bronchoalveolar lavage fluid. Histologic studies showed administration of elecampane camphor reduced inflammatory signs and mucin production in lungs. CONCLUSION The findings provide evidence that elecampane camphor has a potential use as anti‐allergic therapeutics. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Background The root of Saussurea lappa is used in Asian traditional medicine to treat asthma, rheumatism, and other conditions. Extracts of Saussurea lappa were reported to alleviate house dust mite‐induced atopic‐like dermatitis in Nc/Nga mice, and sesquiterpene lactones were isolated. To elucidate whether epiligulyl oxide, a sesquiterpene lactone has beneficial effects on allergic asthma, anti‐asthma effects were studied using female Balb/c mice and rat RBL‐2H3 mast cells METHODS Antigen‐induced degranulation was measured in vitro by measuring β‐hexosaminidase activity. A murine ovalbumin‐induced allergic asthma model was used to test the in vivo efficacy of epiligulyl oxide. RESULTS Antigen‐induced degranulation was inhibited by epiligulyl oxide. Potency Sensitization and challenge of ovalbumin induced allergic asthma responses. Administration of epiligulyl oxide decreased numbers of inflammatory cells, especially eosinophils, and reduced the expression and secretion of Th2 cytokines, including IL‐4 and IL‐13, in lung tissues and bronchoalveolar lavage fluid. Histologic studies showed administration of epiligulyl oxide reduced inflammatory signs and mucin production in lungs. CONCLUSION These findings provide evidence that the epiligulyl oxide has potential use as anti‐asthma therapeutics. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .