Database screening as a strategy to identify endogenous candidate metabolites to probe and assess mitochondrial drug toxicity

摘要: Adverse drug reactions (ADRs) are considered an inherent risk of medication use, and some ADRs have been associated with off-target drug interactions with mitochondria. Metabolites that reflect mitochondrial function may help identify patients at risk of mitochondrial toxicity. We employed a database strategy to identify candidate mitochondrial metabolites that could be clinically useful to identify individuals at increased risk of mitochondrial-related ADRs. This led to l-carnitine being identified as the candidate mitochondrial metabolite. l-carnitine, its acetylated metabolite, acetylcarnitine and other acylcarnitines are mitochondrial biomarkers used to detect inborn errors of metabolism. We hypothesized that changes in l-carnitine disposition, induced by a “challenge test” of intravenous l-carnitine, could identify mitochondrial-related ADRs by provoking variation in l-carnitine and/or acetylcarnitine blood levels. To test …