Impact of Azithromycin on Forsythiaside Pharmacokinetics in Rats:A Population Modeling Method

Objective:Lianhuaqingwen and Shuanghuanglian are drug treatment options for Corona Virus Disease 2019(COVID-19).In China,use of traditional Chinese medicine with Shuanghuanglian or Lianhuaqingwen(for them,forsythiaside is the active antiviral and antibacterial component)in combination with azithromycin is common for the treatment of pediatric pneumonia.It is important to understand the reason why the combination of these compounds is better than a single drug treatment.This study aimed to explore the pharmacokinetic interaction between forsythiaside and azithromycin.Methods:Twelve male Sprague-Dawley rats were randomly divided into an experimental group(Forsythia suspensa extract and azithromycin)and a control group(a single dose of Forsythia suspensa extract in 5%glucose solution).Plasma samples were collected at scheduled time points,and the high-performance liquid chromatography combined with ultraviolet method was used to determine the plasma forsythiaside concentration.Non-compartmental analysis and population pharmacokinetic methods were used to investigate the forsythiaside pharmacokinetic difference between the experimental and control group.Results:Compared with a single administration,the area under the curve and half-life of forsythiaside increased,and forsythiaside clearance decreased significantly after co-administration with azithromycin.The in vivo behavior of forsythiaside could be described by the one compartment model.The forsythiaside clearance decreased when combined with azithromycin.Visual evaluation and bootstrap results suggested that the final model was precise and stable.Conclusion:Co-administration of azithromycin can significantly decrease the forsythiaside clearance and increase drug exposure.A lower dose of azithromycin can obtain sufficient forsythiaside concentration to provide antiviral and antibacterial activity.

Preparation of Forsythiaside-hydroxypropyl-β-cyclodextrin Inclusion Complex and Its Characters

To overcome the chemical instability of forsythiaside,the forsythiaside-hydroxypropyl-β-cyclodextrin inclusion complex was prepared by triturating. The inclusion complex was found having a varied UV spectrum and melt temperature point. Inclusion complex has a higher stability to UV light and temperature over forythiaside itself. Pharmacological evidence showed that inclusion complex has little effect on pharmacokinetics by chicken intravenous injection. This study is favorable for developing preparations for forsythiaside and its clinical application.

Pharmacokinetic interaction of Forsythia suspensa extract and azithromycin injection after single and co-intravenous administration in rats

Azithromycin and Chinese medicine forsythia are often used together to treat pediatric mycoplasma infections in China. We aimed to investigate the pharmacokinetic interaction of Forsythia suspensa extract and azithromycin after single and co-intravenous administration in rats. Male Sprague-Dawley rats received single(Forsythia suspensa extract or azithromycin) treatment or co-administration of Forsythia suspensa extract and azithromycin. Blood samples were collected at scheduled times, and drug concentrations were determined by HPLC-UV or HPLC-MS/MS methods. Both non-compartmental analyses and nonlinear mixed-effects modeling approaches were applied to fit pharmacokinetic data and evaluate the impact of co-administration. Pharmacokinetic analysis showed that the area under the curve of azithromycin and forsythiaside increased, and clearance decreased significantly(P < 0.05),after co-administration. The in vivo behavior of both azithromycin and forsythiaside could be appropriately described by the two-compartmental model. The final population pharmacokinetic model indicated that co-administration decreased the central volume of azithromycin and forsythiaside clearance significantly. Co-administration of Forsythia suspensa extract and azithromycin significantly decreased the clearance and increased exposure for both drugs. Pharmacokinetic data suggest that drug co-administration may increase efficiency.