Ocular toxicity of AUY922 in pigmented and albino rats.

Title

Ocular toxicity of AUY922 in pigmented and albino rats.

Creator

Roman Danielle; VerHoeve James; Schadt Heiko; Vicart Axel; Walker Ursula Junker; Turner Oliver; Richardson Terrilyn A; Wolford Suzanne T; Miller Paul E; Zhou Wei; Lu Hong; Akimov Mikhail; Kluwe William

Publisher

Toxicology and applied pharmacology

Date

2016
2016-10

Description

AUY922, a heat shock protein 90 inhibitor is associated with ocular adverse events (AEs). To provide a better understanding of ocular AEs in patients, 4 investigative studies were performed in a step-wise approach to assess retinal structure and function in pigmented (Brown Norway) and albino (Wistar) rats. In rats administered 30mg/kg of AUY922, the AUC0-24h and Cmax are comparable to that in patients at 70mg/m(2). AUY922 at \textgreater/=30mg/kg was poorly tolerated by rats with morbidity or mortality generally after the third weekly treatment. Electroretinography (ERG) changes were observed at doses \textgreater/=30mg/kg. The ERG changes were dose dependent, consistent with an effect on the photoreceptors, and fully reversible. The ERG effects could not be minimized by decreasing the Cmax while maintaining AUC. Histopathological changes were seen mainly when rats were administered AUY922 at 100mg/kg. The 2-hour infusion of AUY922 at 100mg/kg caused disorganization of the outer segment photoreceptor morphology in male Brown Norway rats; the severity of the disorganization increased with the number of administrations, but was reversible during a 4-week posttreatment period. There was no major difference in ocular response between Brown Norway and Wistar rats. No changes in serum iron levels, and no changes in rhodopsin, PDE6alpha, beta-transducin concentrations, or retinal pigment epithelium-specific protein RPE65 expression were observed after single and multiple infusions of AUY922 at 100mg/kg compared to vehicle-treated controls. AUY922 retinal toxicity in rats recapitulates and further characterizes that reported in patients and is shown to be reversible, while a precise molecular mechanism for the effect was not determined.

Subject

*AUY922; *Electroretinography; *Histopathology; *HSP90 inhibitor; *Ocular toxicity; *Rodents; Animals; Electroretinography; Eye/*drug effects/physiopathology; Isoxazoles/toxicity; Rats; Resorcinols/toxicity; Wistar

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

55–62

Volume

309

Citation

Roman Danielle; VerHoeve James; Schadt Heiko; Vicart Axel; Walker Ursula Junker; Turner Oliver; Richardson Terrilyn A; Wolford Suzanne T; Miller Paul E; Zhou Wei; Lu Hong; Akimov Mikhail; Kluwe William, “Ocular toxicity of AUY922 in pigmented and albino rats.,” NEOMED Bibliography Database, accessed June 19, 2021, https://neomed.omeka.net/items/show/3797.

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