OBJECTIVE To develop physiologically based pharmacokinetic （PBPK） model for sodium tanshinone Ⅱ A sulfonate （STS）， clopidogrel （Clo）， and its metabolites， to predict the potential drug-drug interaction （DDI） between STS and Clo during co-administration， and to identify the key factors influencing the predicte d DDI， and provide evidence for rational clinical medication. METHODS Physicochemical and pharmacokinetic parameters of Clo， its metabolites， and STS were retrieved from PubMed， DrugBank， and SwissADME for PBPK model development. The steady-state area under the plasma concentration-time curve （AUC） and maximum concentration （ c max ） of clopidogrel thiol H4 （Clo-AM） were used as indicators to evaluate the DDI between STS and Clo. Single-factor sensitivity analysis was performed to identify key parameters influencing DDI between STS and Clo during co-administration. RESULTS Compared with Clo alone， after 7 days of Clo combined with STS 40 mg， the AUC ratio and c max ratio of Clo-AM were 0.75 and 0.63， respectively. When the dose of STS was increased to 80 mg， the AUC ratio and c max ratio of Clo-AM were 0.62 and 0.56， respectively. Sensitivity analysis indicated that the absolute values of normalized sensitivity coefficients for the lipophilicity of Clo-AM， the inhibition constants of STS for CYP2C19 and CYP3A4， and the hepatic clearance of Clo-AM were 15.19， 11.34， 10.98， 3.08， respectively. These parameters were the highly sensitive parameters in the DDI between STS and Clo during co-administration. CONCLUSIONS The established PBPK model can be used to predict the DDI between STS and Clo during co-administration. Co-administration of STS and Clo may lead to decreased exposure of Clo-AM. The lipophilicity-related parameters of Clo-AM and the inhibition parameters related to CYP3A4 and CYP2C19 are key parameters influencing the prediction of Clo-AM exposure， among which the inhibitory effects of STS on CYP3A4 and CYP2C19 may be an important mechanism mediating the DDI between STS and Clo.

OBJECTIVE To develop physiologically based pharmacokinetic （PBPK） model for sodium tanshinone Ⅱ A sulfonate （STS）， clopidogrel （Clo）， and its metabolites， to predict the potential drug-drug interaction （DDI） between STS and Clo during co-administration， and to identify the key factors influencing the predicte d DDI， and provide evidence for rational clinical medication. METHODS Physicochemical and pharmacokinetic parameters of Clo， its metabolites， and STS were retrieved from PubMed， DrugBank， and SwissADME for PBPK model development. The steady-state area under the plasma concentration-time curve （AUC） and maximum concentration （ c max ） of clopidogrel thiol H4 （Clo-AM） were used as indicators to evaluate the DDI between STS and Clo. Single-factor sensitivity analysis was performed to identify key parameters influencing DDI between STS and Clo during co-administration. RESULTS Compared with Clo alone， after 7 days of Clo combined with STS 40 mg， the AUC ratio and c max ratio of Clo-AM were 0.75 and 0.63， respectively. When the dose of STS was increased to 80 mg， the AUC ratio and c max ratio of Clo-AM were 0.62 and 0.56， respectively. Sensitivity analysis indicated that the absolute values of normalized sensitivity coefficients for the lipophilicity of Clo-AM， the inhibition constants of STS for CYP2C19 and CYP3A4， and the hepatic clearance of Clo-AM were 15.19， 11.34， 10.98， 3.08， respectively. These parameters were the highly sensitive parameters in the DDI between STS and Clo during co-administration. CONCLUSIONS The established PBPK model can be used to predict the DDI between STS and Clo during co-administration. Co-administration of STS and Clo may lead to decreased exposure of Clo-AM. The lipophilicity-related parameters of Clo-AM and the inhibition parameters related to CYP3A4 and CYP2C19 are key parameters influencing the prediction of Clo-AM exposure， among which the inhibitory effects of STS on CYP3A4 and CYP2C19 may be an important mechanism mediating the DDI between STS and Clo.

Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

OBJECTIVE To establish a liquid chromatography-tandem mass spectrometry （LC-MS/MS） method for the simultaneous determination of bepotastine and hydroxychloroquine concentrations in human breast milk and apply it in clinical practice. METHODS The milk samples （50 μL） were precipitated with 200 μL methanol containing the internal standard （100 ng/mL chloroquine）， and the supernatant was taken for analysis after vortexing and centrifugation. The separation was performed on a Waters ACQUITY UPLC HSS T3 column with mobile phase consisted of 0.1% formic acid-10 mmol/L ammonium acetate solution （phase A） and methanol （phase B） at gradient elution of 0.35 mL/min. The injection volume was 2 μL， and the analysis time was 4 min. The detection of the analytes was performed by electrospray ionization in positive mode by multiple reaction monitoring with the transition of m/z 388.9→201.9 （bepotastine）， m/z 336.3→247.1 （hydroxychloroquine）， and m/z 320.2→247.2 （chloroquine）. The established LC-MS/MS method was researched in methodology and used to determine the drug concentrations in the breast milk of 1 case of lactating patient. RESULTS The linear range of bepotastine was 2-200 ng/mL（ r＝0.999）， and hydroxychloroquine was 50-1 000 ng/mL （r＝0.998）. The intra-assay and inter-assay precisions were both ≤15%， and the accuracy， extraction recovery， matrix effect， and stability all met the acceptance criteria for bioanalytical method validation. The concentration result of bepotastine and hydroxychloroquine in the breast milk of the lactating patient showed， after 2 h and 14 h， the concentrations of bepotastine in the breast milk of the patient were 34.95 ng/mL and 5.72 ng/mL； those of hydroxychloroquine were 211.92 ng/mL and 104.18 ng/mL， respectively. The relative infant doses were 1.83% and 0.56%， respectively. CONCLUSIONS The established method is simple， rapid， and sensitive. It is suitable for simultaneous determination of bepotastine and hydroxychloroquine concentrations in human milk and can provide reference for safe drug use during lactation.

OBJECTIVE To establish a liquid chromatography-tandem mass spectrometry （LC-MS/MS） method for the simultaneous determination of bepotastine and hydroxychloroquine concentrations in human breast milk and apply it in clinical practice. METHODS The milk samples （50 μL） were precipitated with 200 μL methanol containing the internal standard （100 ng/mL chloroquine）， and the supernatant was taken for analysis after vortexing and centrifugation. The separation was performed on a Waters ACQUITY UPLC HSS T3 column with mobile phase consisted of 0.1% formic acid-10 mmol/L ammonium acetate solution （phase A） and methanol （phase B） at gradient elution of 0.35 mL/min. The injection volume was 2 μL， and the analysis time was 4 min. The detection of the analytes was performed by electrospray ionization in positive mode by multiple reaction monitoring with the transition of m/z 388.9→201.9 （bepotastine）， m/z 336.3→247.1 （hydroxychloroquine）， and m/z 320.2→247.2 （chloroquine）. The established LC-MS/MS method was researched in methodology and used to determine the drug concentrations in the breast milk of 1 case of lactating patient. RESULTS The linear range of bepotastine was 2-200 ng/mL（ r＝0.999）， and hydroxychloroquine was 50-1 000 ng/mL （r＝0.998）. The intra-assay and inter-assay precisions were both ≤15%， and the accuracy， extraction recovery， matrix effect， and stability all met the acceptance criteria for bioanalytical method validation. The concentration result of bepotastine and hydroxychloroquine in the breast milk of the lactating patient showed， after 2 h and 14 h， the concentrations of bepotastine in the breast milk of the patient were 34.95 ng/mL and 5.72 ng/mL； those of hydroxychloroquine were 211.92 ng/mL and 104.18 ng/mL， respectively. The relative infant doses were 1.83% and 0.56%， respectively. CONCLUSIONS The established method is simple， rapid， and sensitive. It is suitable for simultaneous determination of bepotastine and hydroxychloroquine concentrations in human milk and can provide reference for safe drug use during lactation.

Objective To optimize the prescription of flaxseed lignans sustained release tables by central composite design-response surface methodology.MethodsWith HPMC, EC and starch dosage as factors, and flaxseed lignans in 2, 6 and 12 h of cumulative release as evaluation indexes, central composite design-response surface optimization method was used to conduct prescription optimization experiments, and optimized prescription analysis was carried out.Results The optimal prescription of flaxseed lignans sustained release tables was as following: HPMC dosage was 43%; EC was 26%; starch content was 17%. Optimized index forecast values were very close to the observed values. In vitro release test of three selected optimal formulations indicated that there existed high approximation between the observed and estimated values.Conclusion It shows that the established model is suitable for flaxseed lignans sustained release tables, which can be used in the optimization of the prescription of flaxseed lignans sustained release tables.