Micropuncture study of the handling of gentamicin by the rat kidney

Senekjian, H. O.; Knight, Thomas F.; Weinman, Edward J.

doi:10.1038/ki.1981.34

Cited by 39 publications

(19 citation statements)

References 15 publications

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“…They also suggest that gentamicin undergoes a bidirectional transport. In fact, this phenomenon has been reported for gentamicin by Senekjian et al (20) and Sheth et al (21) and for netilmicin by Pastoriza-Munoz et al (17). These authors explained the higher fractional excretion and the lower accumulation of netilmicin than of gentamicin in tissue by the fact that the apical membrane transport rate of netilmicin was intrinsically lower than that of gentamicin.…”

Section: Discussionmentioning

confidence: 66%

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Renal disposition of gentamicin, dibekacin, tobramycin, netilmicin, and amikacin in humans

Contrepois¹,

Brion²,

Garaud³

et al. 1985

Antimicrob Agents Chemother

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The tubular disposition of five aminoglycosides was studied in humans to establish a possible relationship between tubular reabsorption and the nephrotoxicity that has been described in the literature. Thirty-three healthy male volunteers received a continuous intravenous infusion of isotonic saline with inulin, followed 1 h later by inulin plus gentamicin, dibekacin, tobramycin, netilmicin, or amikacin (1 mg/kg per h) or amikacin (4 mg/kg per h) over a period of 2 h. Brain-stem-evoked response audiometry was performed both before and at the end of each infusion. The latency of wave V remained constant whichever antibiotic was considered. The glomerular filtration rate did not vary significantly during the infusion of each drug. The percent fractional excretion was 79 + 6, 81 ± 22, 85 5, and 99 ± 9 for gentamicin, dibekacin, tobramycin, and netilmicin, respectively, and 83 4 and 124 13 for amikacin at concentrations of 1 and 4 mg/kg per h, respectively. Net balance and renal clearance were similar for the five aminoglycosides when administered at a rate of 1 mg/kg per h. With gentamicin only, fractional excretion was correlated with the urinary flow rate. We can conclude that (i) gentamicin, generally considered the most nephrotoxic agent, had the highest degree of net reabsorption; (ii) netilmicin exhibited a net zero tubular balance; (iii) amikacin had different patterns of tubular disposition according to the dose, i.e., reabsorption at 1 mg/kg per h and secretion at 4 mg/kg per h, raising the hypothesis of a saturable process of reabsorption; and (iv) these differences in tubular reabsorption could account at least in part for the known different nephrotoxic potentials of these five aminoglycosides in humans.

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Section: Discussionmentioning

confidence: 66%

“…Current knowledge of the renal disposition of aminoglycosides is derived primarily from studies of the tubular transport of gentamicin in animals (12,20,28) or in vitro (15,26,27). To our knowledge, no study so far has compared in humans the tubular disposition of the aminoglycosides most often used in clinical situations.…”

mentioning

confidence: 99%

Renal disposition of gentamicin, dibekacin, tobramycin, netilmicin, and amikacin in humans

Contrepois¹,

Brion²,

Garaud³

et al. 1985

Antimicrob Agents Chemother

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“…In contrast, pyrazinoate does not reduce urate excretion in the rabbit (18). Rabbit proximal tubules secrete urate actively but have no mediated urate reabsorption (19,20 …”

Section: Resultsmentioning

confidence: 99%

Paradoxical effects of pyrazinoate and nicotinate on urate transport in dog renal microvillus membranes.

Guggino¹,

Aronson

1985

J. Clin. Invest.

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“…No labeling was seen on the basolateral membranes of proximal tubular cells. Several studies reported that aminoglycoside uptake via the basolateral membrane of proximal tubular cells may contribute to the overall cellular accumulation of these drugs (2,12,14). Williams and Hottendorf (18), using isolated brush border and basolateral membrane vesicles, showed that the basolateral as well as the brush border surfaces of proximal tubular cells may contribute significantly to the renal accumulation of aminoglycosides.…”

Section: Discussionmentioning

confidence: 99%

“…The uptake of aminoglycosides by proximal tubular cells has been demonstrated by different approaches such as micropuncture (11,14) and autoradiographic experiments (3,15,17). The association of aminoglycosides with lysosomes of cortical renal cells has been shown by subcellular fractionation (16).…”

Section: Discussionmentioning

confidence: 99%

Subcellular distribution of gentamicin in proximal tubular cells, determined by immunogold labeling

Beauchamp

Gourde

Bergeron

1991

Antimicrob Agents Chemother

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The subcellular distribution of gentamicin in rat renal proximal tubular cells was evaluated by immunogold labeling. The distribution of the drug was monitored from 10 min to 10 days following single (40 mg/kg of body weight) and multiple (5 and 20 mg/kg/12 h) injections of gentamicin. Animals were killed on day 11, and cubes of renal cortex tissue were fixed overnight in cold phosphate-buffered glutaraldehyde (0.5%), dehydrated in ethanol, and embedded in Araldite 502 epoxy resin. Ultrathin sections were made and incubated with sheep antigentamicin and then with protein A-gold (15 nm) complex. At 10 min after a single injection, the labeling was found over the brush border membrane and over the membranes of endocytic apical vesicles of proximal tubular cells. After 1 h, a similar distribution was observed and the labeling was also seen over small lysosomes located close to the brush border membrane. At 24 h, gold particles were found over large lysosomes of proximal tubular cells. Following 10 days of treatment, lysosomes of proximal tubular cells were densely labeled with gold particles. The labeling was distributed uniformly over the lysosomes, although a lower density of labeling was observed over the myeloid bodies inside the lysosomes. Necrotic proximal tubular cells showed labeling over intact lysosomes and also in the cytoplasms of the cells, in the mitochondria, and in the nucleoli. The various control experiments demonstrated the high specificity of these results. The present immunocytochemical study better documents the subcellular disposition of gentamicim in proximal tubular cells, as previously evaluated by subcellular fractionation and autoradiography. This technique will be useful for better understanding the relationship between drug disposition and drug-induced toxicity.The nephrotoxicity of aminoglycosides has been extensively investigated, but the mechanism by which these drugs induce cellular disturbances and necrosis remains to be elucidated. These drugs, which are essentially eliminated by glomerular filtration, are partially reabsorbed by proximal tubular cells (15). They concentrate into lysosomes (7), where they induce a lysosomal phospholipidosis (9) characterized by the appearance of myeloid bodies (8).The incorporation of aminoglycosides within the lysosomes of renal cortical cells has been demonstrated by subcellular fractionation (16). The binding of aminoglycosides to brush border membranes and their subsequent accumulation into lysosomes of proximal tubular cells have been previously shown by autoradiography (3, 15). Moreover, Giurgea-Marion et al. (7), by using subcellular fractionation, have observed that gentamicin remains associated with the lysosomes of proximal tubular cells throughout a 9-day treatment.The objective of the present study was

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Micropuncture study of the handling of gentamicin by the rat kidney

Cited by 39 publications

References 15 publications

Renal disposition of gentamicin, dibekacin, tobramycin, netilmicin, and amikacin in humans

Renal disposition of gentamicin, dibekacin, tobramycin, netilmicin, and amikacin in humans

Paradoxical effects of pyrazinoate and nicotinate on urate transport in dog renal microvillus membranes.

Subcellular distribution of gentamicin in proximal tubular cells, determined by immunogold labeling

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