Introduction: Over the past decade, zebrafish have been tasked to play important roles from modeling human diseases to finding cures for them. Inadvertently, these fish now find themselves swimming along the drug development pipeline. A number of studies have been conducted to see if these small fish are up to the task of drug toxicity testing, an important rite of passage along the pharmaceutical pipeline. Areas covered: This review covers the recent publications (2008 – 2010) on the state-of-the-art applications that couple advanced technologies with the unique advantages of zebrafish for drug toxicity screening. The paper looks at the several automated high-throughput platforms that have been developed for zebrafish teratogenicity, cardiotoxicity and neuro-sensory organ toxicity assays over the past 3 years as well as the important studies related to metabolism and biotransformation of selected drugs that have been initiated. This paper also reviews their mechanistic and predictive omics applications. Expert opinion: While there have been a number of developments over the past 3 years and indeed over the last 10 years, challenges and limitations still exist, which, unless overcome, will prevent zebrafish from truly reaching their full potential as a drug toxicological model. That being said, recent developments have suggested that zebrafish could play a role in bridging the gap between in vitro cell-based models and in vivo mammalian models.

The zebrafish model has been increasingly explored as an alternative model for toxicity screening of pharmaceutical drugs. However, little is understood about the bioactivation of drug to reactive metabolite and phase I and II metabolism of chemical in zebrafish as compared with human. The primary aim of our study was to establish the bioactivation potential of zebrafish using acetaminophen as a probe substrate. Our secondary aim was to perform metabolite profiling experiments on testosterone, a CYP3A probe substrate, in zebrafish and compare the metabolite profiles with that of human. The glutathione trapping assay of N-acetyl-p-benzoquinone imine demonstrated that zebrafish generates the same reactive metabolite as humans from the bioactivation of acetaminophen. Zebrafish possesses functional CYP3A4/5-like and UDP-glucuronosyltransferase metabolic activities on testosterone. Differential testosterone metabolism was observed among the two species. In silico docking studies suggested that the zebrafish CYP3A65 was responsible for the bioactivation of acetaminophen and phase I hydroxylation of testosterone. Our findings reinforce the need to further characterize the drug metabolism phenotype of zebrafish before the model can fully achieve its potential as an alternative toxicity screening model in drug research.

Background: Conventionally, vancomycin trough levels have been used for therapeutic drug monitoring (TDM). Owing to the increasing evidence of trough levels being poor surrogates of area under the curve (AUC) and the advent of advanced pharmacokinetics software, a paradigm shift has been made toward AUC-guided dosing. This study aims to evaluate the impact of AUC-guided versus trough-guided TDM on vancomycin-associated nephrotoxicity. Methods: A systematic review was conducted using PubMed, Embase, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Google scholar, and Cochrane library databases; articles published from January 01, 2009, to January 01, 2021, were retrieved and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Studies that evaluated trough-guided or AUC-guided vancomycin TDM and vancomycin-associated nephrotoxicity were included. Random-effects models were used to compare the differences in nephrotoxicity. Results: Of the 1191 retrieved studies, 57 were included. Most studies included adults and older adults (n = 47, 82.45%). The pooled prevalence of nephrotoxicity was lower in AUC-guided TDM [6.2%; 95% confidence interval (CI): 2.9%–9.5%] than in trough-guided TDM (17.0%; 95% CI: 14.7%–19.2%). Compared with the trough-guided approach, the AUC-guided approach had a lower risk of nephrotoxicity (odds ratio: 0.53; 95% CI: 0.32–0.89). The risk of nephrotoxicity was unaffected by the AUC derivation method. AUC thresholds correlated with nephrotoxicity only within the first 96 hours of therapy. Conclusions: The AUC-guided approach had a lower risk of nephrotoxicity, supporting the updated American Society of Health-System Pharmacists guidelines. Further studies are needed to evaluate the optimal AUC-derivation methods and clinical utility of repeated measurements of the AUC and trough levels of vancomycin.

Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are analgesics used for moderate to severe pain in many animals, including reptiles. However, reptilian dosing regimens are often extrapolated from other animal species. This is not ideal as inter- and intra-species variability in physiology may result in varied drug disposition. Therefore, this critical review aims to collate data from pharmacological studies of selected NSAIDs and opioids performed in reptile and provide an analysis and discussion on the existing pharmacodynamic knowledge and pharmacokinetic data of NSAIDs and opioids use in reptiles. Additionally, key pharmacokinetic trends that may aid dosing of NSAIDs and opioids in reptiles will also be highlighted. Most of the existing reports of NSAID used in reptiles did not observe any adverse effects directly associated to the respective NSAID used, with meloxicam being the most well-studied. Despite the current absence of analgesic efficacy studies for NSAIDs in reptiles, most reports observed behavioural improvements in reptiles after NSAID treatment. Fentanyl and morphine were studied in the greatest number of reptile species with analgesic effects observed with the doses used, while adverse effects such as sedation were observed most with butorphanol use. While pharmacokinetic trends were drug- and species-specific, it was observed that clearance (CL) of drugs tended to be higher in squamates compared to chelonians. The half-life (t_1/2) of meloxicam also appeared to be longer when dosed orally compared to other routes of drug administration. This could have been due to absorption-rate limited disposition. Although current data provided beneficial information, there is an urgent need for future research on NSAID and opioid pharmacology to ensure the safe and effective use of opioids in reptiles.