Cinoxacin: Pharmacokinetics and the Effect of Probenecid

Israel, Karen; Black, Henry R.; Nelson, Robert L.; Brunson, M.K.; Nash, J. P.; Brier, G. L.; Wolney, J. D.

doi:10.1002/j.1552-4604.1978.tb01577.x

Cited by 15 publications

(4 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Serum and urinary levels, as well as pharmacokinetic parameters of Cinoxacin determined in this study are in agreement with the data reported in the literature (1,2,3, 6,7,13,15,20). For pipemidic acid however we have found a larger percentage of urinary recovery (83% over 24 h) than cited by Humbert et al (12) (63% over 24 h) or Soussy et al (22) (48.3% over 24 h).…”

Section: Discussionsupporting

confidence: 82%

Comparative pharmacokinetic profiles of Cinoxacin and pipemidic acid in humans

Jm¹,

Comte²,

Lavillaureix³

1983

European Journal of Drug Metabolism and Pharmacokinetics

View full text Add to dashboard Cite

Serum and urinary levels of Cinoxacin and pipemidic acid were determined at 7-day intervals in the same 10 healthy volunteers after a single oral dose of respectively 500 and 400 mg of the drugs. Comparison of results shows that Cinoxacin was absorbed faster (absorption half-life, ta 1/2cin = 0.25 h) than pipemidic acid (ta 1/2pip = 0.37 h) and distributed in a smaller apparent volume (AVDcin = 23.5 1/1.73 m2; AVDpip = 60.1 1/1.73 m2). Biological half-lives were identical (tb 1/2cin = 2.10 h; tb 1/2pip = 2.15 h). On the other hand, serum levels for Cinoxacin at 1, 2 and 4 hours (8.1 +/- 1.5 micrograms/ml, 10.6 +/- 1.5 micrograms/ml, 5.6 +/- 1.3 micrograms/ml respectively) were higher than those for pipemidic acid (3.3 +/- 0.3 micrograms/ml, 3.4 +/- 0.5 micrograms/ml, 2.1 +/- 0.5 micrograms/ml respectively). Urinary excretion of the two derivatives during the 12 hours following their administration was similar (Ucin0-12h = 86%; Upip0-12h = 83%). Mean urinary concentrations were particularly high, still attaining respectively 90 +/- 29 micrograms/ml and 131 +/- 38 micrograms/ml in samples collected between the 9th and the 12th hours; these levels were well above the M.I.C. for the Gram-negative organisms included within the spectrum of activity of these two quinolones. In addition, predictive calculations of serum levels reached after multiple dosing indicate that at an administration rate of 500 mg every 6 or preferably every 4 hours, Cinoxacin concentrations should be sufficiently high to be of interest in the treatment of systemic infections by sensitive organisms.

show abstract

Section: Discussionsupporting

confidence: 82%

Comparative pharmacokinetic profiles of Cinoxacin and pipemidic acid in humans

Jm¹,

Comte²,

Lavillaureix³

1983

European Journal of Drug Metabolism and Pharmacokinetics

View full text Add to dashboard Cite

show abstract

“…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.…”

mentioning

confidence: 99%

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

Shimada¹,

Yamaji²,

Ueda³

et al. 1983

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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...

show abstract

“…Tubular secretion has been observed with nalidixic acid (10), piromidic acid (10), miloxacin (10), and norfloxacin (22) in rabbits; pipemidic acid (12) in dogs; and cinoxacin (11,20), norfloxacin (22), and ciprofloxacin (25) in humans.…”

Section: Discussionmentioning

confidence: 99%

Renal handling of fleroxacin in rabbits, dogs, and humans

Shiba

Saitô

Shimada

et al. 1990

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The renal handling of fleroxacin was studied by renal clearance and stop-flow techniques in rabbits and dogs and by analyzing the pharmacokinetics with and without probenecid in humans. In rabbits the excretion ratios (fleroxacin intrinsic renal clearance/glomerular filtration rate) were greater than unity (2.01) without probenecid and were decreased to a value below unity (0.680) with probenecid. In dogs, on the other hand, the excretion ratios were less than unity (0.608 and 0.456) both without and with probenecid, and so were not affected by probenecid. This fact suggested that fleroxacin was excreted into urine by both glomerular filtration and renal tubular secretion in rabbits, but only by glomerular ifitration in dogs, accompanied by partial renal tubular reabsorption in both species; these mechanisms were also supported by stop-flow experiments. In humans probenecid treatment induced increases in the elimination half-life and area under the serum concentration-time curve and decreases in apparent serum clearance, renal clearance, and urinary recovery of fleroxacin. The excretion ratio without probenecid was 1.13, which was significantly decreased to 0.750 with probenecid. These results indicated that both renal tubular secretion and reabsorption contributed to renal excretion of fleroxacin in humans. The contribution of tubular secretion was species dependent and was extensive in rabbits, nminimal in dogs, and moderate in humans. Renal tubular reabsorption was commonly found in every species. The long elimination half-life of fleroxacin in humans might be explained by its small total serum clearance and small renal clearance, which are attributed to less tubular secretion and more tubular reabsorption.Fleroxacin (AM-833; Ro 23-6240), a new trifluorinated quinolone, has potent and broad in vitro activity against gram-positive and gram-negative bacteria and also exhibits significant in vivo activity against various experimental infections after oral administration (5, 9, 16). Pharmacokinetic studies in laboratory animals (14, 15) demonstrated that fleroxacin is rapidly and completely absorbed from the gastrointestinal tract and is well distributed to various tissues, except the brain. Animals with larger body weights tend to show a longer elimination half-life of fleroxacin, except rabbits, which show a short half-life. Pharmacokinetic studies in healthy volunteers revealed that fleroxacin is metabolized to a small extent and is characterized pharmacokinetically by a long elimination half-life and high concentration in plasma (17,24,26). This drug was principally excreted into urine by laboratory animals and humans (15,17,24,26). Little is known, however, on the mechanism of renal excretion of fleroxacin. Many reports that have been published on the renal handling of quinolones showed different mechanisms, depending on the animal species and drugs (1, 10-13, 19, 20, 22, 25). Shimada et al. (22) found species differences in the renal handling of norfloxacin in rabbits, dogs, and humans.The purpose of the pr...

show abstract

Cinoxacin: Pharmacokinetics and the Effect of Probenecid

Cited by 15 publications

References 8 publications

Comparative pharmacokinetic profiles of Cinoxacin and pipemidic acid in humans

Comparative pharmacokinetic profiles of Cinoxacin and pipemidic acid in humans

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

Renal handling of fleroxacin in rabbits, dogs, and humans

Contact Info

Product

Resources

About