The Pharmacokinetics And Pharmacodynamics Of Cotrimoxazole In Portunus Trituberculatus And Sarafloxacin In Eriocheir Sinensis

This paper is mainly divided into three parts. The first part reported in-vitro andin-vivo pharmacodynamics of sulfamethoxazole (SMZ) and trimethoprim (TMP) to thepathogenic vibrios of sea animal source. The second part studied the pharmacokineticsof SMZ and TMP in hemolymph of Portunus trituberculatus following oraladministration. The distribution and elimination of SMZ and TMP were alsoinvestigated in hepatopancreas, muscle and gill of Portunus trituberculatus. In the thirdpart, pharmacokinetics and pharmacodynamics of sarafloxacin hydrodrochloride inEriocheir sinensis were investigated following oral administration, andpharmacokinetics/pharmacodynamics (PK/PD) parameters were calculated. Mainresults are as follows:1. In-vitro and in-vivo pharmacodynamics of SMZ and TMP to seawater vibriosThe minimal inhibitory concentration(MIC) to44strains of seawater vibrios withdifferent ratios of SMZ:TMP=1:0,0:1,50:1,20:1,10:1,5:1,2:1,1:1,1:2,1:5weredetected using broth microdilution method. Selecting the minimum MIC value ofSMZ:TMP ratio, and having an anti-vibrio-infection test to Portunus trituberculatuswith the selected SMZ:TMP ratio and the ratio of SMZ:TMP=5:1. The results showedthat the range of MIC values was0.3125~5μg/mL with SMZ:TMP=1:1, and there were32strains in MIC=0.3125μg/mL and0.625μg/mL, better than the other nine ratios ofSMZ:TMP. There were19strains in MIC=0.3125μg/mL and0.625μg/mL withSMZ:TMP=5:1. In the anti-vibrio-infection test, there were more survival crabs ofgroup SMZ:TMP=1:1than group SMZ:TMP=5:1with the same injected concentrationof vibrio liquid. The results of in-vitro and in-vivo pharmacodynamics showed thatantibacterial effect with SMZ:TMP=1:1was better compared with SMZ:TMP=5:1 under the equal amount of total SMZ and TMP.2. The pharmacokinetics, tissue distribution and elimination of SMZ and TMP inPortunus trituberculatusThe pharmacokinetics of SMZ and TMP in hemolymph of Portunus trituberculatuswere investigated following oral administration with SMZ:TMP=5:1andSMZ:TMP=1:1using RP-HPLC. The crab were kept in seawater with salinity of20andtemperature of28.0±1.0℃. The tissue distribution and elimination of SMZ and TMPwere also analyzed in hepatopancreas, muscle and gill.The concentration vs. time data were analyzed by statistical moment principle,and the pharmacokinetic parameters are as follows: the peak time (Tmax) of SMZ ingroup SMZ:TMP=5:1and group SMZ:TMP=1:1were both4h; the peak concentration(Cmax) were64.974mg/L and46.188mg/L, respectively; area under curve (AUC0-∞)were1975.449mg h/L and1367.183mg h/L, respectively; volume of distribution (Vz/F)were1.528L/kg and1.338L/kg, respectively; elimination half-time (T1/2z) were25.127h and25.35h, respectively; average residence time from zero to infinity (MRT0-∞)were30.832h and26.668h, respectively. Tmaxof TMP were4h and6h, respectively;Cmaxwere0.622mg/L and1.371mg/L, respectively; AUC0-∞were25.444mg h/L and62.862mg h/L, respectively; Vz/F were42.272L/kg and34.793L/kg, respectively;T1/2zwere44.633h and30.314h, respectively; MRT0-∞were66.232h and46.232h,respectively. The results suggested that SMZ and TMP were quickly absorbed inPortunus trituberculatus, and TMP was widely distributed than SMZ. Peakconcentration of TMP in group SMZ:TMP=1:1was about2times of that in groupSMZ:TMP=5:1.The concentration vs. time data of SMZ and TMP in hepatopancreas, muscle andgill were all analyzed by statistical moment principle. The parameters of SMZ were asfollows: Tmaxof group SMZ:TMP=5:1were all4h; Cmaxwere51.979mg/kg,45.807mg/kg and45.972mg/kg, respectively; AUC0-∞were1659.91mg h/kg,1565.275mg h/kg and1450.696mg h/kg, respectively; T1/2zwere27.369h,16.921h and21.055h,respectively; Tmaxof group SMZ:TMP=1:1were2h,4h and4h, respectively; Cmaxwere19.960mg/kg,22.253mg/kg and25.429mg/kg, respectively; AUC0-∞were660.339mg h/kg,564.332mg h/kg and949.593mg h/kg, respectively; T1/2zwere34.763h,19.254h and18.302h, respectively. The parameters of TMP were as follows: Tmaxof group SMZ:TMP=5:1and group SMZ:TMP=1:1were all4h; Cmaxof groupSMZ:TMP=5:1were90.992mg/kg,2.389mg/kg and7.337mg/kg, respectively;AUC0-∞were2500.585mg h/kg,82.198mg h/kg and193.630mg h/kg, respectively;T1/2zwere18.679h,26.572h and27.688h, respectively. Cmaxof TMP in groupSMZ:TMP=1:1were141.280mg/kg,5.352mg/kg and10.075mg/kg, respectively;AUC0-∞were1892.59mg h/kg,110.384mg h/kg and211.605mg h/kg, respectively;T1/2zwere18.116h,49.682h and28.501h, respectively. The results suggested that SMZand TMP were quickly absorbed and eliminated in hepatopancreas, muscle and gill.SMZ was distributed evenly among the three tissues, but TMP was mainly distributed inhepatopancreas. In muscle and gill, the concentration of TMP was substantially below10mg/kg. According to SMZ and TMP residues in muscle, a recommended withdrawaltime was16d when administered with SMZ:TMP=5:1; and a recommended withdrawaltime was14d when administered with SMZ:TMP=1:1. According to pharmacokinetics,pharmacodynamics and withdrawal time, the best pharmacy ratio was SMZ:TMP=1:1for vibriosis of Portunus trituberculatus.3. Pharmacokinetics and pharmacodynamics of sarafloxacin hydrodrochloride inChinese Mitten Crab, Eriocheir sinensisThe pharmacokinetics of sarafloxacin hydrochloride in male and female crab wasinvestigated following oral administration (30mg/kg) using RP-HPLC. The minimuminhibitory concentrations of sarafloxacin hydrochloride on the pathogenic Aeromonaswere detected. The pharmacokinetics/pharmacodynamics (PK/PD) parameters werecalculated. The haemolymph sarafloxacin hydrochloride concentration vs. time for maleand female crab were best described by a two-compartment model with first absorption.Tmaxfor male and female crab were4h, and Cmaxwere （5.619±1.192）mg/L and（7.775±1.426）mg/L, respectively, V/F were3.801L/kg and2.871L/kg, respectively.Sarafloxacin was widely distributed in the female and male crab. T1/2β、CL/F andAUC0-tfor male crab were51.982h,0.138L/h/kg and209.1mg h/L, respectively. Thecorresponding value for female crab were55.956h,0.087L/h/kg and325.5mg h/L,respectively. The MIC of sarafloxacin on the pathogenic Aeromonas hydrophila HX1b1,Aeromonas veronii CMX313and CMX4from Eriocheir sinensis were0.5mg/L,0.25mg/L and0.25mg/L, respectively. The Cmax/MIC of strain HX1b1on male and femalecrab were15.55and11.24, respectively, and the AUC0-24/MIC were197and145.4, respectively. The Cmax/MIC of strains CMX313and CMX4were31.1and22.48,respectively, and the AUC0-24/MIC were394and290.8, respectively. It shows that thepharmacokinetics of sarafloxacin hydrochloride in male and female crab have somedifference but not significant.The dosage of30mg/kg by medicated feed can effectivelycombat bacterial diseases caused by the Aeromonas.