Elyse C Freiberger, Michael P Thompson, Xiaomei Zhang, Essence B Underwood, Thomas L Lynch, Gary J Jenkins, David S Wagner
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引用次数: 0
Abstract
In vitro systems such as cultured hepatocytes are used early in drug development as a proxy for in vivo data to predict metabolites in human and the potential preclinical species. These data support preclinical species selection for toxicity studies as well as provide early evidence for potential active and reactive metabolites that can be generated in human. Although in vivo data would be best to select preclinical species for a given compound, only in vitro systems are available when selecting toxicity study species. However, as with any in vitro system, the correlation to actual in vivo results can be variable. Understanding the reliability of predicting in vivo metabolites from the various available in vitro assays and determining which system may be most predictive would help de-risk drug development teams' selection process. In this manuscript, we address these questions: can in vitro systems predict circulating metabolites? If so, is predictivity quantitative or indicative of what levels may be seen circulating? Of the currently available in vitro systems, is one better than the others at generating predictive metabolites? To address the first two issues (general in vitro/in vivo predictivity, and whether any in vitro/in vivo correlations are quantitative), we used historical data from Abbott/AbbVie to compare in vitro metabolite profiles with metabolite profiles from in vivo absorption, distribution, metabolism, excretion, and clinical studies. In this retrospective analysis of historic metabolite profiling data, in vitro systems predicted ∼50% of circulating metabolites present in vivo, across preclinical species and human, with no correlation between apparent concentrations in vitro versus in vivo. To address the final question, we selected 10 commercially available compounds with published metabolism data and incubated them in five common in vitro systems (microsomes, liver S9, suspension hepatocytes, HμREL cocultured hepatocytes, and hepatocyte spheroids); the new in vitro metabolite profiling data were compared against published in vivo data to determine whether any individual system was more accurate in generating known major human circulating metabolites. Suspension hepatocytes and cocultured hepatocytes marginally outperformed the other systems. Current in vitro systems have value early in development when in vivo studies are not feasible and are required for regulatory filings to support preclinical toxicology species selection but should not be treated as wholly representative of a given drug's in vivo metabolism. SIGNIFICANCE STATEMENT: This is a comprehensive assessment of historic metabolism data quantitating the success rate of in vitro to in vivo predictivity. Reliability of in vitro systems for metabolite profiling is important for early drug development, and understanding predictivity will help give appropriate context to the data. New data were also generated to compare common in vitro liver models to determine whether any could be definitively identified as more predictive of human circulating metabolites than others.
期刊介绍:
An important reference for all pharmacology and toxicology departments, DMD is also a valuable resource for medicinal chemists involved in drug design and biochemists with an interest in drug metabolism, expression of drug metabolizing enzymes, and regulation of drug metabolizing enzyme gene expression. Articles provide experimental results from in vitro and in vivo systems that bring you significant and original information on metabolism and disposition of endogenous and exogenous compounds, including pharmacologic agents and environmental chemicals.