The Effects Of Probenecid On The Acute Toxicity,Tissue Distribution And Pharmacokinetics Of Amoxicillin

Amoxicillin(AMX) is a semisynthetic parahydroxyl analogue of penicillin with a broad spectrum of antibacterial activity and bactericidal action,however,it has short half eleminete time(T1/2) which is a drawback for antibiotics . Probenecid(PB) is a uricosuric agent that acts to competiviely inhibit active renal tubular secretion in the kidney, It has been proved to be able to prolong the T1/2 of ampicillin and increase the level of blood drug. Therefore the interaction of PB and AMX (AMX+PB) was made to prolong the period of therapy. This studies can provide the data for the clinic use of AMX + PB.The simple method of calculating LDso was used to study the effect of PB on the acute toxicity of AMX,The result showed that the toxicity of PB+AMX or AMX is very low,and there was no effect of PB on the on the acute toxicity of AMX.Mouse was used to study the effect of PB on the the tissue distribution of AMX , The concention of AMX in test samples was measured ,using the agar plate diffusion meathod of Bennet et a/,using BaxiXXua aoptiXicr as the test organism. The results showed that minimal detectable level was 0.039 u g /m 1 ,0.078 ug /ml respectively for AMX in phosphate buffer solution(PBS) ,and for the tissue such as heart,liver,lung,kidney or small intestine . The coefficient of variation value of the standard were lower than10%, and the rediscovery rates were more than 85%. The results also showed that AMX was apparently well distributed in tissues of mouse,and PB inhibited the distribution of AMX to the liver and kidney,but increased the distribution to the heat,lung and small intestine.A test of different ratios between PB and AMX was made to consider wether there exists the saturable nature of PB kinetics,using the microbiological method to detect AMX .The comparation of kinetics values of AMX showed that the weights ratio of 1:1 of PB and AMX is the best choice.The main objective of this study was to determine the effect of PB on the pharmacokinetics of AMX in healthy pigs. Five healthy pigs were used in a randomized design. In repeated experiments all pigs were administered of 10 mg of AMX per kg body weight by intramus and 7 days later they were administered of 10 mg of PB per kg body weight by intramuscular , followed immediately by 10 mg AMX per kg body weight by intramuscular. A rapid and sensitive assay for AMX in pig plasma was developed using reversed phase high performance liquid chromatography (HPLC). The results were as follows: The peak of AMX was well isolated from the extraneous peaks. And the analytical recovery of AMX from plasma was >82.5%, and the relative standard deviations for within-day and between-day were <5.00% and <10.98% For treatment with AMX alone , the elimination half time(T1/2) was 0.86+0.18h(mean+standard deviation), AUC was 12.38+5.69 u g/ml.h , the peak levels of amoxocillin in plasma averaged 7.21 +3.27 u g/ml at 0.19 + 0.11 h. And preceding treatment with PB resulted in a increase in both T1/2(2.77+ 1. 02hr) (P<0.05) and AUC(35.24+18.62 u g/ml.h).