Kinetics of gentamicin uptake and release in the rat. Comparison of inner ear tissues and fluids with other organs.

Abstract

The kinetics of entry and release of gentamicin was investigated in fluids and tissues of the inner ear of the rat, as well as in renal cortex, and in organs that do not share susceptibility to the toxic effects of aminoglycosides. Various modes of administration were used to achieve different patterns of drug plasma concentrations. Electrophysiological and histological examinations were performed to correlate pharmacokinetics and ototoxicity. Results show that: the uptake of the drug by the inner ear tissues is dose dependent and manifests a rapid saturation kinetics with a concentration plateau of about 1 micrograms/mg of protein. The low ratio of the perilymph and endolymph to plasma concentrations argues against the concept of an accumulation of the drug in the inner ear over drug levels in plasma, which has been considered as the basic mechanism of ototoxicity. In renal cortex, the kinetics appears similar to that of the inner ear but the concentrations achieved are 10-fold higher than in cochlear tissues. In other organs (liver, heart, lung, and spleen), no saturation could be demonstrated within the duration of the experiment. Ototoxicity seems to be related to the penetration of the drug into compartment(s) from which the half-life of disappearance is extremely slow. Rapid uptake, early saturation, and long exposure of the tissues to the drug may account for the development of toxicity in inner ear and kidney.

Uptake of fluorescent gentamicin by vertebrate sensory cells in vivo

“…Subsequent studies confirmed the rapid uptake of aminoglycosides into the organ of Corti and endocochlear fluids within 2 h following a single injection (Tran Ba Huy et al, 1986;Tran Ba Huy et al, 1983). More recent studies have used fluorescent probes, immunohistochemistry, autoradiography and electron microscopy to localize aminoglycosides in hair cells up to six months after administration (de Groot et al, 1990;Dulon et al, 1993;Hashino et al, 1997;Imamura and Adams, 2003a;Richardson et al, 1997).…”

“…Initial studies of tritiated aminoglycoside uptake showed rapid uptake in endocochlear tissues, cells, and fluids within 2 h (Balogh et al, 1970;Tran Ba Huy et al, 1986;Tran Ba Huy et al, 1983;von Ilberg et al, 1971). Tritiated aminoglycosides cannot distinguish between cytoplasmic and organelle uptake, except by electron microscopy (Hashino et al, 1997;Wedeen et al, 1983), precluding the analysis of subcellular distribution of aminoglycoside uptake in large numbers of individual cell types.…”

Local inner-ear drug delivery and pharmacokinetics

“…Pharmacokinetic studies have confirmed this principle (9,34,44,45,46,47). Potential side effects of systemic treatment and complications from a long lasting, higher dose therapy can be avoided through topical application therapy.…”

Hsp70 inhibits aminoglycoside-induced hearing loss and cochlear hair cell death

“…Studies in rats have shown that aminoglycosides can be found in the inner ear only minutes after systemic administration and levels plateau within 30 min to 3 h (Tran Ba Huy et al 1986). Clearance of aminoglycosides from both inner ear fluids and tissues is very slow: While the half-life of aminoglycosides in serum is about 3-5 h, they can remain in the inner ear for longer than 30 days (Tran Ba Huy et al 1986).…”

“…Clearance of aminoglycosides from both inner ear fluids and tissues is very slow: While the half-life of aminoglycosides in serum is about 3-5 h, they can remain in the inner ear for longer than 30 days (Tran Ba Huy et al 1986). When exposed to aminoglycosides, hair cells demonstrate both morphologic and molecular features of apoptotic cell death, including condensed, marginated chromatin, and positive terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining (Forge and Fradis 1985;Li et al 1995;Lang and Liu 1997;Nakagawa et al 1998;Forge and Li 2000;Matsui et al 2002;Mangiardi et al 2004).…”