AIM: To investigate the effects and quantitative relations of co-administering probenecid OF different dosages on
pharmacokinetics
of cefaclor in rabbits and approach the possible mechanisms involved as well.METHODS: Monitor plasma and urine cefaclor concentrations.24 male rabbits were randomly divided into 4 groups by Cefaclor 50(mg·kg~(-1)),Cefaclor 50(mg·kg~(-1))+Probenecid 100(mg·kg~(-1)),Cefaclor 50(mg·kg~(-1))+Probenecid 250(mg·kg~(-1)) and Cefaclor 50(mg·kg~(1))+Probenecid 625(mg·kg~(-1)).Blood and urine samples were collected according to the regular time schedule after intragastric administration.The concentration of cefaclor in blood and urine were determined by HPLC.Pharmacokinetic parameters were calculated by DAS(Drug and Statistical) software.Measur plasma protein-binding rate of cefaclor.The experimental groups and drug dosage were same as described above.The blood sample was drawn at 1 hour after administration,and the protein-binding rate of cefaclor was determined by
equilibrium dialysis.RESULTS: Within the dosages of probenecid ranged from 0-250(mg·kg~(-1)),T_(1/2ka),T_(max),C_(max) and AUC of cefaclor increased in accordance with increasing dosage of co-administering probenecid while CL/F and Vd/F were decreased(P<(0.01));However,when the dosage of co-administering probenecid was 625(mg·kg~(-1)),C_(max) of cefaclor strikingly decreased(P<(0.01)),while AUC and CL/F maintained at the levels of those with probenecid 250(mg·kg~(-1)).In this experiment,urinary excretive peak time of cefaclor in its prototype postponed gradually,biological half life prolonged and urinary excretive accumulation percentage decreased obviously(P<(0.01)).To the dosages of probenecid ranging from 0-250(mg·kg~(-1)),protein-binding rate of cefaclor decreased notably(P<(0.01))going with increasing dosages of co-administration probenecid;While the dosage of co-administration probenecid reached 625(mg·kg~(-1)),the protein-binding rate of cefaclor corresponded to that of cefaclor 50(mg·kg~(-1)) without probenecid(P>(0.05)).CONCLUSION: Co-administering probenecid can strikingly change
pharmacokinetics of cefaclor and the influential degree of pharmacokinetics parameters is dependent on dosages of probenecid used in the experiment.Biological half life prolongs and urinary excretive accumulation percentage of cefaclor decreases obviously.