Mechanisms and pharmacokinetic/pharmacodynamic profiles underlying the low nephrotoxicity and ototoxicity of etimicin

Abstract

Etimicin (ETM), a fourth-generation aminoglycosides (AGs), is now widely clinically used in China due to its high efficacy and low toxicity. However, the mechanisms underlying its low nephrotoxicity and ototoxicity remain unclear. In the present study we compared the antibacterial and toxicity profiles of etimicin, gentamicin (GM, a second-generation AG), and amikacin (AMK, a third-generation AG), and investigated their pharmacokinetic properties in the toxicity target organs (kidney and inner ear) and subcellular compartments. We first demonstrated that ETM exhibited superior antibacterial activities against clinical isolates to GM and AMK, and it exerted minimal nephrotoxicity and ototoxicity in rats following multi-dose administration. Then, we conducted pharmacokinetic studies in rats, showed that the three AGs accumulated in the kidney and inner ear with ETM being distributed to a lesser degree in the two toxicity target organs as compared with GM and AMK high-dose groups. Furthermore, we conducted in vitro experiments in NRK-52E rat renal tubular epithelial cells and HEI-OC1 cochlear hair cells, and revealed that all the three AGs were distributed predominantly in the mitochondria with ETM showing minimal accumulation; they not only directly inhibited the activity of mitochondrial complexes IV and V but also inhibited mitochondrial function and its related PGC-1α-NRF1-TFAM pathway; ETM caused minimal damage to the mitochondrial complex and mitochondrial biogenesis. Our results demonstrate that the minimal otonephrotoxicity of ETM results from its lesser accumulation in mitochondria of target cells and subsequently lesser inhibition of mitochondrial function. These results provide a new strategy for discovering novel AGs with high efficacy and low toxicity.

Mechanism and Prevention of Ototoxicity Induced by Aminoglycosides

“…On the other hand, because of the obvious differences in pharmacokinetics and drug elimination between animals and humans, it is not effective to calculate drug dosage by body weight. In addition to the above protective agents, aminoglycosides with low ototoxicity such as etimicin can also be used, which can effectively reduce ototoxicity (Yao et al, 2020 ). At the same time, new alternative drugs can be developed to reduce ototoxicity.…”

Beneficial effects of time‐restricted feeding on gentamicin cytotoxicity in mouse cochlea and vestibular organs

“…22 Based on this previous study, we hypothesized that TRF could affect the toxicity of GM to the cochlea and vestibular endorgans because renal tubular cells have clinical similarities with inner ear cells. 23,24 To our knowledge, there is no report on the beneficial effects of TRF on GM ototoxicity and vestibulotoxicity.…”

Prevención y diagnóstico precoz de la sordera por ototóxicos Recomendaciones CODEPEH 2020

“…Una opción sería el desarrollo y la utilización de variantes de fármacos con menor toxicidad. Por ejemplo, la etimicina es un antibiótico aminoglucósido de cuarta generación, que se emplea actualmente en la práctica clínica en China debido a su alta eficacia y que ha demostrado una oto-nefrotoxicidad mínima, resultado de su menor acumulación en las mitocondrias de las células diana (Yao et al, 2020). Otros antibióticos aminoglucósidos con menor toxicidad en estudio son la apramicina y la gentamicina C1 (Ishikawa et al, 2019).…”