| Cefuroxime lysine,a second generation cephalosporins in the form of lysine salt for cefiuroxine,has been investigated in preclinic,so as to recognize the pharmacokinetic profiles and metabonomics of cefuroxime lysine in vivo.Methods for the concentration assay in biological matrix were developed and validated,meanwhile the theory of population pharmacokinetics and metabolomics was applied to study the population pharmacokinetic modelling of cefuroxime lysine under the conditions of various dosages,acute liver or kidney injxury model and long-term repeated dosages.Metabonomic methods for profiling of blood metabolic changes after 30 d repeated administration for cefuroxime lysine were investigated,and the potential toxic biomarkers were indentified,providing the basis for its safe,effective and suitable application in clinic.1.Stability and decomposition kinetics of cefuroxime lysineThe thermal decomposition of a new antibiotic agent,cefuroxime lysine,was investigated by thermogravimetry analysis(TGA)and differential scanning calorimetry(DSC)methods in anoxic and oxidative environments.By the methods of Kissinger and Flynl-Wall-Ozawa,the thermal kinetic parameters were calculated.From the experimental results,it was obvious that the TG curves could be migrated,both in nitrogen or air atmospheres,toward the higher temperature side with an increase of heating rates.The activation energy of cefiuroxi?e lysine are 122.8 kJ/mol,127.8 kJ/mol in nitrogen or air atmospheres.The degradation kinetics of cefuroxime lysine in aqueous solution were investigated by a developed liquid chromatograph/mass spectrometry(LC/MS)method with pH ranging from 1.5 to 11.0.The influences of pH,temperature,ionic strength,irradiation and oxidation on the degradation rate were evaluated,and the corresponding kinetic parameters were calculated.The decomposition of cefuroxime lysine was observed to follow first order kinetics under all the experimental conditions,and the rate constant increased with an increase in the temperature,ionie strength and oxidation concentrations.The maximum stability was observed in the pH region from 3.6 to 9.0.The irradiation showed obvious effect on the stability.The activation energy was determined to be 116.0 kJ/mol,with the half-life(t1/2)to be 211.3 h at 25?,respectively.2.Bioequivalence and population pharmacokinetics of cefuroxime lysineA rapid,accurate and sensitive UPLC-MS/MS method was developed and fully validated for the bioavailability and bioequivalence study of cefuroxime lysine after intravenous infusion at low,middle and high dosage in beagle dogs.Nonlinear mixed effect model(NONMEM)software was applied to investigate the population pharmacokinetic modelling of cefuroxime lysine,so as to achieve final population pharmacokinetic formulas and its corresponding population pharmacokinetic parameters.The lower limit of quantitation of this method was 0.01 ?g/mL with a wider linear range of 0.01?400 ?g/mL.The absolute-bioavailability of cefuroxime lysine versus cefuroxime sodium was 1.05±0.18,which agree with the criterion of bioequivalence.Cefuroxime lysine showed the linear pharmacokinetic characteristics over the adminnistration of 20?80 mg/kg.The basic pharmacokinetic model was three-eompartmental model,with the final population pharmacokinetics of cefuroxime lysine for Cl1,CI2 and CI3 were 3.74,29.5 and 0.308 mL/h,respectively.3.PK of various administrating routes and PPK of various models of cefuroxime lysineA rapid,accurate and sensitive UFLC-MS/MS method via acidified protein precipitation was developed and validated to investigate the pharmacokinetic profiles by different administrating routes(incliding single intravenous,intraperitoneal,and intramuscular administration)and different models(including normal,acute liver injury and acute kidney injury rats)after intravenous administration.The pharmacokinetics for three administrating routes metioned above were as follows:AUC0-? 45.29 ± 5.42,58.12±15,47,55.31 ± 16.57 mg·h/L;t1/2 0.56 ± 0.32,0.62 ± 0.64,0.75 ± 0.55 h;MRT 0.37±0.07,0.93 ± 0.10,0.65 ± 0.05 h,respectively.While the pharmacokinetics for three models metioned above were as follows:AUC0-? 9.45 ± 14.03,82.3 ±14.5,395.4 ±115.6mg·h/L t1/2 0.69 ± 0.25,0.41 ± 0.07,3.46 ± 1.80 h:MRT 0.68 ± 0.16,0.49 ± 0.08,2.921±1.02 h,respectively.After NONMEM analysis,the population pharmacokinetics for three models were as follows:C1 were 0.890,0.827,0.177 L/h/kg,V1 were 0.463,0.275,0.407 L/kg,V2 were 0.296,0.223,0.156 L/kg,Q were 0.097,11.17,0.067 L/h/kg,respectively.4.Toxicooicokinetics and population pharmacokinetics of cefuroxime lysineTo investigate the toxicokinetics of cefuroxime lysine after ip administration of 675 mg/kg for 1 d,and lasting for 15 and 30 d,so as to evaluate the toxicokinetic profiles in rats.The main toxicokinetic parameters of ceffiroxime lysine were as follows:AUC0-t were 575.8±148.3,410.8 ± 120.2,603.4±158.6 mg/L·h;Cmax were 275.0±102.2,200.4±87.0,355.6±89.3 mg/L;MRT0-t were 1.47±0.29,1.43 ± 0.29,1.14 ± 0.21 h,respectively.There were no significant differences in main pharmacokinetic parameters after single dosing and multiple dosing,indicating no accumulation of drug after multiple dosing caused by cefuroxime lysine.The results of tissue distribution indicated that the concentration in different tissues and organs were as follows:kidney>liver>lung>spleen/muscle>testicle>heart>train.The basic model for population pharmacokinetics was two-compartmental model,with the final population pharmacokinetics of cefuroxime lysine for Cl1,Cl2 were 0.900,3.67 mL/h and V1,V2 were 0.217,0.624 mL,respectively.5.Toxic biomarkers identified based on after long term toxic administrationUsing UPLC-MS method based metabonomics,the variance of metabolites in plasma caused by long-term cefuroxime lysine administration were investigated.The results of metabononics suggested that the blood LPC and phenylalanine etc as the possible toxic biomarkers. |
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