Mechanism of renal excretion of AM-715, a new quinolonecarboxylic acid derivative, in rabbits, dogs, and humans

Abstract

The mechanisms of the renal excretion of AM-715, a synthetic antimicrobial agent, were studied in rabbits, dogs, and humans. In both rabbits and humans, clearance was greater than creatinine clearance and was profoundly decreased by the administration of probenecid. Thus, in these subjects, AM 715 was cleared by both tubular secretion and glomerular filtration. In dogs, however, the excretion ratio (close to unity), biological half-life, and stop-flow pattern of AM-715 were not affected by probenecid, indicating that the renal excretion of AM-715 took place mostly through glomerular filtration. These results suggest that renal excretion of AM-715 differs with animal species.AM-715, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid, is a new synthetic antibacterial agent with a broad spectrum of activity covering both gram-positive and gram-negative organisms (6, 9). In humans, AM-715 is eliminated predominantly by renal excretion and is metabolized only to a small extent (13). Little is known, however, of the mechanisms by which AM-715 is excreted and, specifically, whether it is actively secreted by the renal tubules in a fashion similar to that of such organic acids as nalidixic acid (7), piromidic acid (7), pipemidic acid (10), miloxacin (7), or cinoxacin (8,14). The purpose of the present study was to examine the mechanism of renal excretion of AM-715 in rabbits, dogs, and humans. To facilitate this evaluation, AM- MATERIALS AND METHODS Renal clearance in rabbits. Five male Japanese White rabbits, weighing 2.8 to 3.4 kg, were used. They were anesthetized with 30 mg of pentobarbital sodium per kg of body weight, administered in the vein of the foreleg. Urine was collected through a cannula inserted in the left ureter. The left femoral artery and auricular vein were catheterized with polyethylene tubes for sampling of blood and administration of drug solution, respectively. A polyethylene catheter was placed in the aorta through the right femoral artery, and blood pressure was monitored by a pressure transducer (type MP4T; Nihon Koden, Ltd.). The urinary bladder was cannulated for the drainage of accumulating urine. After completion of these surgical preparations by methods described previously (5), an intravenous infusion of 10%o mannitol (JP IX; Towa Kasei Kogyo Co., Ltd.) in isotonic saline (solution I) was started at the rate of 1.0 mllmin. When urine flow had stabilized, urine was collected during a 5-min interval, and blood was taken at the midpoint of the interval. Each sample was used as a blank for determining the concentration of inulin, which was injected intravenously through the auricular vein at a priming dose of 40 mg/kg and sustained by the infusion of 0.12% inulin solution in solution I (solution II) at the rate of 1.0 ml/min. After 60 min of the infusion, urine and blood were collected as a blank for the determination of AM-715 concentration. Then, AM-715 was infused at the rate of 0.13 mg/kg per min. The infusion solution was prepared by mixing a 5% aqueous sol...

Pharmacokinetics of temafloxacin in humans after multiple oral doses

“…Tubular transport of enoxacin, norfloxacin, ciprofloxacin, and ofloxacin has also been inferred by high CLR/CLCR ratios or has been confirmed by demonstration of significant reductions in CLR when coadministered with probenecid, an inhibitor of anionic tubular transport (5,18,23,25,28,29). Even fleroxacin, which has a CLR/CLCR ratio below unity, appears to have probenecid-sensitive tubular secretion (22).…”

Competitive inhibition of renal tubular secretion of ciprofloxacin and metabolite by probenecid

“…Its [6,18,19]. For several quinolones, such as norfloxacin [9], fleroxacin [10], enoxacin [11], levofloxacin [7,8] and gatifloxacin [6], a reduction in renal clearance with probenecid was found.…”

“…Probenecid has been reported to inhibit active transport of both anionic and cationic drug molecules at various sites in the body [3][4][5]. Furthermore, it is well known to decrease the renal secretion of numerous quinolones such as gatifloxacin [6],levofloxacin [7,8],norfloxacin [9],fleroxacin [10] and enoxacin [11]. Moxifloxacin and sparfloxacin are not affected by probenecid [12,13].…”

Issues Related to the Use of Canines in Toxicologic Pathology—Issues With Pharmacokinetics and Metabolism

“…Renal tubular secretion is mediated by active transport systems specific for acids and bases. Species similarities (24,64) and differences (24,47,57,58) in renal secretion have been found to exist. Renal tubular reabsorption is the third component of renal excretion and can be either an active or passive process.…”