{"doi":"10.3389/fphar.2024.1363545","title":"In vivo screening for toxicity-modulating drug interactions identifies antagonism that protects against ototoxicity in zebrafish","abstract":"Introduction: Ototoxicity is a debilitating side effect of over 150 medications with diverse mechanisms of action, many of which could be taken concurrently to treat multiple conditions. Approaches for preclinical evaluation of drug-drug interactions that might impact ototoxicity would facilitate design of safer multi-drug regimens and mitigate unsafe polypharmacy by flagging combinations that potentially cause adverse interactions for monitoring. They may also identify protective agents that antagonize ototoxic injury. Methods: To address this need, we have developed a novel workflow that we call Parallelized Evaluation of Protection and Injury for Toxicity Assessment (PEPITA), which empowers high-throughput, semi-automated quantification of ototoxicity and otoprotection in zebrafish larvae via microscopy. We used PEPITA and confocal microscopy to characterize in vivo the consequences of drug-drug interactions on ototoxic drug uptake and cellular damage of zebrafish lateral line hair cells. Results and discussion: By applying PEPITA to measure ototoxic drug interaction outcomes, we discovered antagonistic interactions between macrolide and aminoglycoside antibiotics that confer protection against aminoglycoside-induced damage to lateral line hair cells in zebrafish larvae. Co-administration of either azithromycin or erythromycin in zebrafish protected against damage from a broad panel of aminoglycosides, at least in part via inhibiting drug uptake into hair cells via a mechanism independent from hair cell mechanotransduction. Conversely, combining macrolides with aminoglycosides in bacterial inhibition assays does not show antagonism of antimicrobial efficacy. The proof-of-concept otoprotective antagonism suggests that combinatorial interventions can potentially be developed to protect against other forms of toxicity without hindering on-target drug efficacy.","journal":"Frontiers in Pharmacology","year":2024,"id":478497,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9612,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1317612,"name":"Emma Mudrock","orcid":null,"position":1,"is_corresponding":false},{"id":1317613,"name":"Elizabeth M. Nilles","orcid":null,"position":2,"is_corresponding":false},{"id":1317306,"name":"Andrea McQuate","orcid":"0000-0002-2052-2004","position":3,"is_corresponding":false},{"id":1317614,"name":"Monica Bergado","orcid":null,"position":4,"is_corresponding":false},{"id":1317615,"name":"Alden Gu","orcid":null,"position":5,"is_corresponding":false},{"id":1317616,"name":"Louie Galitan","orcid":null,"position":6,"is_corresponding":false},{"id":1317617,"name":"Natalie Gleason","orcid":null,"position":7,"is_corresponding":false},{"id":1317618,"name":"Henry C. Ou","orcid":null,"position":8,"is_corresponding":false},{"id":465616,"name":"David W. Raible","orcid":"0000-0002-5342-5841","position":9,"is_corresponding":false},{"id":378977,"name":"Rafael E. Hernandez","orcid":"0000-0003-4408-7411","position":10,"is_corresponding":false},{"id":88585,"name":"Shuyi Ma","orcid":"0000-0003-0783-1328","position":11,"is_corresponding":false},{"id":1193989,"name":"Ethan Bustad","orcid":"0000-0002-0230-2913","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-19T02:06:46.330532Z","pmid":"38515847","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}