Renal handling of fleroxacin in rabbits, dogs, and humans

Abstract

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...

Fleroxacin pharmacokinetics in aqueous and vitreous humors determined by using complete concentration-time data from individual rabbits

“…Systemic probenecid administration prolongs the half-life of P-lactam antibiotics in the vitreous humor because of a putative action on the retinal transport pump (6). Since the renal tubular secretion of fleroxacin in rabbits is markedly inhibited by probenecid (34), we examined the effect of systemically administered probenecid on fleroxacin elimination. Fleroxacin was injected directly into the vitreous humor.…”

“…However, the rate of elimination from the vitreous humor following both routes was extraordinarily rapid relative to that for other antimicrobial agents (28) and was not shortened by the coadministration of probenecid. In rabbits, the elimination of fleroxacin is more rapid than that in humans because of the increased metabolism and active tubular secretion which is blocked by probenecid (20,34). Rapid entry and elimination of fleroxacin in the vitreous humor indicates that elimination occurs through the retina (23).…”

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.…”

“…For example, carnivores tend to have urine with a more acidic pH and may re-absorb basic compounds less thoroughly than herbivores. Again, as seen with other renal excretory processes, species differences in reabsorption can occur (28,57). Despite the complex interplay of the components of the renal excretory process, several investigators have been successful in performing allometric scaling using the renal excretion parameters of several species, including dogs.…”

“…However, caution is advised even when studying the renal excretion within a single class of molecules. The quinolone antibiotics have been shown to exhibit both species and compound dependent differences in absorption and secretion with little correlation (57). Certainly, the best recipe for success in extrapolating between species is achieved with a detailed understanding of the physicochemical properties of the drug and the renal physiology of the animal species.…”