CLINICAL PROBLEMS ON THE BINDING OF PROTEIN TO ANTITUBERCULOUS DRUGS

Abstract

Studies on the protein binding of antituberculous drugs were carried out by using equilibrium dialysis method to clarify several clinical problems on the interaction between drugs and protein.
The results were as follows:
1) The factors related to the protein binding rates of sera to PAS were the concentration of drugs and protein in sera, the ratio of the volume in external and internal compartments, etc. As nearly the same binding rates of serum protein to PAS were obtained both in vivo and in vitro under the same PAS concentration, the data in this report were obtained mainly by in vitro method.
2) The binding rates of sera to antituberculous drugs were generally low values, while RFP and PAS showed relatively higher rates than other drugs.
3) Marked individual variations were observed in the binding rates of sera to PAS and. RFP, and the binding rates of sera to PAS significantly correlated with the concentration of albumin in sera, while such a significant correlation was not seen in the case of RFP. The significant correlation however, was found between the binding ratio of RFP and the concentration of cholesterol in sera. The binding rates and binding index of sera to PAS in patients showing PAS-allergy were significantly higher than that in patients showing no PAS-allergy.
4) Eight drugs were tested as serum binding displacing agents and it was found that PAS was displaced only by phenylbutazon and dichlorfenack Na in high concentration of 300μg/ml.
5) Significant negative correlation was seen between the binding rates of sera to PAS and the rates of acetylation of PAS.
6) EB scarcely bound to sera, while it showed relatively high binding rates to blood cells. As EB concentration in cells was higher and its duration was longer than those in sera when EB was administered orally, it was suggested that the maintenance of EB concentration in blood was attributed to the binding of EB to cells. There were some individual variations on the RFP binding rates to cells, and a case of tuberculosis showing the highest rate had attack of pancytopenia.
7) No marked correlation was found between the drug concentration in tissues and the binding rates of EB or RFP to each tissue in rat, administered orally these drugs, while the concentration of several chemotherapeutic agents in tissues could be estimated by measuring the binding rates of drugs by in vitro experiment.
8) The binding rates of EB to tissues in rat administered EB orally increased markedly with time. This facts suggested that the binding rate of EB metabolite were markedly higher than that of EB, and it was necessary to measure the binding rates of drug metabolite to tissues for the purpose of studying the mechanism of side effect from the standpoint of protein binding.