Comparative pharmacokinetics of aminoglycoside antibiotics in guinea pigs

The kinetics of the entry of three aminoglycosides into inner-ear tissues of the guinea pig after acute and chronic administration were compared: gentamicin toxic to the cochlea and the vestibule, amikacin preferentially cochleotoxic, and netilmicin of low ototoxic liability. During constant intravenous infusion, levels of the three drugs in plasma tended to reach a plateau after 1 h, while levels in perilymph did not reach a plateau within 6 h. The drug concentrations in both vestibular and cochlear tissues quickly reached saturation. Amikacin and gentamicin concentrations were similar in vestibular and cochlear tissues, while netilmicin values were somewhat lower. After 1 week of chronic treatment (100 mg of drug per kg of body weight daily subcutaneously), levels of gentamicin and amikacin in tissue were similar to each other and were not significantly different between cochlear and vestibular tissues. Netilmicin concentrations again were somewhat lower in the tissues, but identical to those of the other drugs in the perilymph. After 3 weeks of treatment, all of the drugs were equally distributed in the inner-ear tissues. Release of the drug from the tissues after the 3-week treatment was faster for amikacin (83% decrease after 20 days) than for netilmicin and gentamicin (approximately 50% decrease). There was no correlation, under any of the experimental conditions, between the drug concentrations and their degrees of toxicity. These results demonstrate that selective aminoglycoside ototoxicity cannot be explained by a preferential uptake or accumulation of drugs in the afflicted tissues or in the perilymph.Toxicity to both the vestibular and cochlear structures of the inner ear is a well-known adverse effect of aminoglycoside antibiotic therapy. The morphological changes and electrophysiological dysfunctions induced by different aminoglycosides have been extensively studied, and it is clearly established that the pattern of toxicity varies greatly within this family of antibiotics (1,8,12). For example, gentamicin affects the cochlear and vestibular systems to nearly the same extent, while amikacin preferentially damages the cochlea; netilmicin is significantly less toxic than either gentamicin or amikacin to both parts of the labyrinth (2, 5, 7). It has been postulated that this differential damage is related to the concentration of aminoglycoside achieved in the perilymph, i.e., the more toxic a drug, the higher its level in this inner-ear fluid (7,20), although exceptions from this pattern had been noted (6, 15). Moreover, it has been argued that an accumulation of aminoglycosides in the inner-ear fluids is responsible for the organ-specific toxic action. However, recent detailed pharmacokinetic studies have not supported such an explanation of toxicity. Levels of aminoglycosides in inner-ear fluid did not exceed levels in plasma (21,22

Section: Discussioncontrasting

confidence: 57%

Comparative uptake of gentamicin, netilmicin, and amikacin in the guinea pig cochlea and vestibule

Dulon¹,

Aran²,

Zajic³

et al. 1986

“…bolus injection of the four aminoglycosides tested appeared to produce the same pharmacokinetics, expressed by the beta half-life, distribution volume, and total body clearance (17). In guinea pigs, however, netilmicin has been shown to exhibit a greater volume of distribution in the central compartment and a greater total body clearance than gentamicin (7). Values of aminoglycoside binding to serum proteins ranging from 0 to 20% have been reported in humans and animals (19).…”

Section: Discussionmentioning

confidence: 99%

Gentamicin, netilmicin, dibekacin, and amikacin nephrotoxicity and its relationship to tubular reabsorption in rabbits

Brion¹,

Barge²,

Godefroy³

et al. 1984

The role of the tubular reabsorption of aminoglycosides in nephrotoxicity was considered. The tubular reabsorption rate, fractional reabsorption, and net balance, expressed as the excreted to infused aminoglycoside ratio, were concomitantly studied in male rabbits by continuous infusion of gentamicin, netilmicin, dibekacin, and amikacin. Aminoglycoside nephrotoxicity was evaluated by creatinine levels in serum and pathological renal damage after 14 days of a low-or high-dose regimen, comprising either eight, hourly intramuscular injections of gentamicin, netilmicin, or dibekacin (4 mg/kg) or amikacin (16 mg/kg); twelve, hourly intramuscular injections of gentamicin, netilmicin, or dibekacin (15 mg/kg) or amikacin (60 mg/kg); or injections of saline for the control group. Aminoglycosides exhibited three degrees of tubular reabsorption: gentamicin had the highest, netilmicin had the lowest, and dibekacin and amikacin had intermediate degrees of reabsorption. Nephrotoxicity associated with alteration in renal histology was observed with gentamicin and, to a lesser extent, with dibekacin in the high-dose regimen. No nephrotoxicity was noted with netilmicin or amikacin compared with the control group. Concentrations of the aminoglycosides in renal cortex and serum were not predictive of renal toxicity. Except for amikacin, which appeared to exhibit the lowest intrinsic renal toxicity, nephrotoxicity was correlated with the tubular reabsorption of each aminoglycoside. It was concluded that aminoglycoside renal toxicity can be determined by two major factors: importance of transport into tubular cells and intrinsic intracellular toxicity.Aminoglycoside nephrotoxicity has been the subject of many clinical, pharmacological, and biochemical investigations (16,20,28). Although the nephrotoxic potential of these drugs varies from one species to another, similar pathological patterns have generally been observed in both humans and animals. Morphological lesions, mainly of the proximal tubular cells (10,25), have been demonstrated by light and electron microscopy. In animal models, differences in aminoglycoside nephrotoxicity were identified some time ago, particularly when, on a weight basis, the doses were 10 to 25 times those used in humans. Under these conditions, gentamicin exhibited greater nephrotoxicity than netilmicin, tobramycin, dibekacin, or amikacin (11,14,25,27). The available evidence indicates that the nephrotoxic potential of aminoglycosides cannot be correlated with peak or trough levels in serum (3). Aminoglycoside accumulation in rat parenchyma was recently correlated with gentamicin and tobramycin nephrotoxicity (1). However, the importance of tissue accumulation per se in the pathogenesis of nephrotoxicity remains uncertain (14,25,27). By using a mathematically derived pharmacokinetic model, Schentag et al. (22) concluded that the extent of timed renal cortical accumulation correlated with clinical toxicity in humans. This renal cortical accumulation reflected the uptake of aminoglycosides exclusively in...

“…Many investigators believe that the inner ear damage is related to the concentration of AG in the perilymph (1,3,5,8,12,14). Although the rates of entry of AG into perilymph are much slower than those of AG into plasma, these drugs seem to accumulate in the perilymph after repetitive dosing because of their slow elimination rates from this body fluid.…”

mentioning

confidence: 99%

“…While trying to determine the kinetics of amikacin in perilymph, we wanted to reduce the number of animals required to establish the various rate constants. Since the perilymph compartment is both small and poorly accessible, generally only a single data point can be obtained from each animal (3,15). We recently modified a radioimmunoassay technique so that only 1 ,ul of perilymph sample is required (4).…”

mentioning

confidence: 99%

Effect of pentobarbital anesthesia on amikacin concentrations in plasma and perilymph and evaluation of multiple sampling in perilymph of guinea pigs

Desjardins-Giasson¹,

Beaubien²,

Cauchy³

1985

The purpose of this study was to determine whether a multiple-sampling procedure could be used in guinea pigs to study the kinetics of amikacin in perilymph. Amikacin was infused intravenously for 6 h into conscious anesthetized guinea pigs, and the concentrations of the drug in plasma and perilymph were measured. From each anesthetized guinea pig, five to six perilymph samples were collected from one ear, and one sample was collected from the other ear at 6 h. The concentrations of amikacin in perilymph were dose proportional and increased slowly during the 6-h infusion. However, after 6 h of intravenous infusion, the concentrations of amikacin in perilymph of the multiply sampled ears were significantly higher than those of the singly sampled ears, indicating that the multiple-sampling procedure should not be used as is to study the kinetics of amikacin in perilymph. Amikacin concentrations in perilymph were linearly related to amikacin concentrations in plasma in pentobarbital-anesthetized animals, as had previously been observed for conscious guinea pigs. However, the slope of the regression line was only 0.09 for anesthetized animals compared with 0.24 for conscious animals. Drug concentrations in plasma were found to be threefold higher in anesthetized animals, whereas drug levels in perilymph were the same in both groups at similar dosing rates. These results indicate that the amikacin concentration in perilymph is not solely dependent upon its concentration in plasma and that other factor(s) can affect the entry of amikacin into the inner ear.Ototoxicity is a well-known adverse effect of aminoglycoside antibiotics (AG). Many investigators believe that the inner ear damage is related to the concentration of AG in the perilymph (1,3,5,8,12,14). Although the rates of entry of AG into perilymph are much slower than those of AG into plasma, these drugs seem to accumulate in the perilymph after repetitive dosing because of their slow elimination rates from this body fluid.Investigators in our laboratory are presently trying to determine the relationship between ototoxicity and the concentrations of amikacin in the perilymph and plasma of guinea pigs. While trying to determine the kinetics of amikacin in perilymph, we wanted to reduce the number of animals required to establish the various rate constants. Since the perilymph compartment is both small and poorly accessible, generally only a single data point can be obtained from each animal (3, 15). We recently modified a radioimmunoassay technique so that only 1 ,ul of perilymph sample is required (4). This small size made multiple sampling of the perilymph feasible in an anesthetized animal. 350 g were used. Food and water were provided ad libitum. Room temperature (21 to 22°C), humidity (50 to 55%), and light cycle (12 h on, 12 h off) were kept constant throughout the experiment.The control group consisted of 19 conscious guinea pigs which had undergone jugular cannulation 48 h previously. Each animal received one of the following i.v. doses of amikacin for 6...