DISTRIBUTION OF CHEMOTHERAPEUTICS AND ANTIBIOTICS IN EXPERIMENTAL PYELONEPHRITIC KIDNEY

Abstract

It is accepted that efficacy of drug treatment for pyelonephritis is partly dependent on drug concentration in the affected kidney tissue. However, function of the pyelonephritic kidney is deteriorated and drug distribution in the affected kidney may alter itself by the grade of renal damage.
This paper presents the study on distribution of some abtibiotics and a sulfonamide drug in experimental pyelonephritic kidneys by determining the drug concentrations in cortex, medulla and papilla, compared with those in normal kidneys when normal treatment doses were applied. Experimental pyelonephritis was produced by intracardial inoculation of E. coli or Citrobacter strain to rats of Wistar species combined with external renal massage.
Distribution of sulfisomesole was studied in experimental E. coli pyelonephritis.
Concentration of the drug in the kidney was remarkably decreased to almost half compared with the control, and concentration gradient from cortex to papilla was also declined significantly. Insoluble acetylated compounds of the sulfonamide were determined in inflamed and normal renal tissue. Acetylation rate in affected kidney was markedly increased in two or three times, compared to the control kidney.
The same studies as on the sulfonamide were carried out on tetracyclines and cephalosporin derivatives in experimental pyelonephritic using a strain of Citrobacter.
Four analogues of tetracyclines, namely tetracycline, oxytetracycline, chlortetracycline and N-pyrrolinidomethyltetracycline were used in this study. The distribution of oxytetracycline, which had high renal clearance, and chlortetracycline, which was poorly excreted from the kidney, were compared with the normal and infected kidney. These two drugs showed remarkably poor distribution among the infected kidney, and above this, concentration gradient from cortex to papilla was also declined in these two drugs. On the other hand, distribution of tetracycline and N-pyrrolinidomethyltetracycline in the inflamed kidney showed no significant difference compared with the control kidney.
Distribution of cephalosporin derivatives or cephaloridine and cephalothin was studied in the same way as the previous drugs.
Cephaloridine is mostly eliminated by glomerular filtration and cephalothin by tubular excertion. In normal group, cephalothin was eliminated more rapidly than cephaloridine. In pyelonephritic group, the accumulation of these two drugs into the kidney was restricted and concentration gradient of the drugs from cortex to papilla was remarkably declined. The enzymatic activity of this strain was not so high determined by iodmetric assay in vitro. From these facts, low diffusion of these drugs in infected kidney tissue is attributed to both pathophysiologic condition of the pyelonephritic kidney and enzymatic inactivation of the antibiotics by β-lactamase produced by this strain.
The above studies showed no difference on drug diffusion among these three kinds of drugs or sulfonamide, tetracyclines and cephalosporins, in spite of the different excretion mechanism from the kidney respectively. However, it should be emphasized that no reasonable elevation of BUN was observed in the entire group at the time the study was performed.
Considering these results, to maintain effective level of the drug in the pyelonephritic kidney, larger dosis should be administered.
However, the susceptibility of the inflamed kidney to nephrotoxicity of antibiotics or chemotherapeu tics should be kept in mind.