Pharmacokinetics Of Sinomenine In Rabbit Plasma And Synovial Fluid Via Different Administration Routes

Objectives:To utilize microdialysis to study the pharmacokinetics of sinomenine (SN) in articular cavity via intramuscular and oral administration. We simultaneously observed the SN pharmacokinetics in rabbit plasma and concentration in articular cavity with electroporation and electric heating administration.Methods:The effect of flow rates and concentrations on the in vitro and in vivo relative recovery(RR) of SN was detected by gain and by loss. Changes of the in vitro and in vivo RRwith the continuation of sampling time was also investigated.24healthy New Zealand rabbits were randomly divided into four groups.50mg/kg SN were administrated via intramuscular injection, orally, electroporation and electric heating, respectively. Plasma and microdialysates from articular cavity were collected. UFLC-MS/MS was utilized to determine the concentration of SN in the samples.Results:The RR of SN in vitro and in vivo decreased as the flow rates increases. The RR of SN were independent of dialyseis direction and drug concentrations (21-420ng/mL), and in vitro and in vivo RR have good stability in13h. When the flow rate is1.5μL/min, the in vitro RR of SN was22.7%, and the in vivo RR was18.7%.The concentration-time curve of SN in rabbit plasma by intramuscular administration was fitted to a two-compartment model. Cmax was9181.67±1884.18ng/mL, T1/2ka was0.15±0.06h, T1/2aα0.77±0.28h, T1/2β2.40±0.21h. While the The concentration-time curve of SN in rabbit plasma by oral administration was found to conform to one-compartment model with Cmax2867.5±246.76ng/mL, T1/2ka was0.31±0.1Oh, T1/2was3.27±0.50h. The kinetics of SN eliminition in synovial fluid by intramuscular and oral administration were one-order Kinetics. Cmax were2764.71±375.70ng/mL and1874.688±477.19ng/mL, Ka were5.28=1=1.86h-1and3.6±0.75h-1,T1/2were3.03±0.68h and3.91±1.48h,respectively. AUCO∞of SN in plasma was3915.038±537.727ng-min/mL by electroporation transdermal delivery which was twice higher compared with electric heating administration. By electroporation administration,SN went into plasma more rapidly with higher Cmax,and Cmax was29.333±4.865ng/mL which was three times of electric heating delivery.Concentration of SN in synovial fluid by electroporation administration were higher than that of electric heating group during75-135min. Concentration of SN in synovial fluid was higher than that of plasma by electroporation administration which illustrated that SN can be enriched in target tissue with electroporation dilevery Conclusion:The concentration-time curve of SN in rabbit plasma was fitted to a two-compartment model with first order elimination and The concentration-time curve of SN in synovial fluid was found to conform to one-compartment model by intramuscular administration. The concentration-time curve of SN in rabbit plasma and synovial fluid were both fitted to a one-compartment model with first order elimination by oral administration. SN went into plasma and synovial fluid more rapidly by intramuscular administration. T1/2were equivalent by the two administration routes in both matices and T1/2was approximately3h.SN can be dilevered into articular cavity by electroporation administration, and which can increase transdermal delivery efficiency of SN compared with electric heating. Moreover, SN can be enriched in target tissue with electroporation dilevery. However, concentration of SN in synovial fluid was much lower by electroporation dilevery compared with systemic administration.Howto enhance the transdermal delivery efficiency of electroporation dilevery needs more study.