Current conceptsII. Selective accumulation of MPP+ in the substantia nigra: A key to neurotoxicity?
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Opportunities and challenges related to saturation of toxicokinetic processes: Implications for risk assessment
2021, Regulatory Toxicology and PharmacologyCitation Excerpt :In situations where there is a lack of a quantifiable relationship between free plasma concentration and adverse effect at the target site, it is more appropriate to use other dose metrics, such as tissue or even cell concentrations of the toxicologically critical penultimate moiety(moieties). For example, 1-methyl-4-phenylpyridinium (MPP+), the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), selectively targets dopaminergic cells of the substantia nigra where the compound has been shown to accumulate in primates, despite being eliminated in other parts of the brain (Irwin and Langston, 1985). This selective concentration of the toxic moiety illustrates the importance and feasibility of selecting a dose metric that is most relevant for the observed toxicity; in this example, the toxic moiety is metabolite substantia nigra concentration rather than blood AUC of the parent.
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2021, Basic Principles of Drug Discovery and DevelopmentA new human pyridinium metabolite of furosemide, inhibitor of mitochondrial complex I, is a candidate inducer of neurodegeneration
2019, Biochemical PharmacologyCitation Excerpt :Is this inhibition specific and persistent? The comparison with MPTP/MPP+ biodistribution studies in mice and monkeys [37,38], or with haloperidol and its pyridinium metabolites in human [25] reinforce the possibility for PoF resulting from furosemide metabolism, to cross the blood-brain-barrier and reach specific areas in the brain. Indeed, results from our in vivo investigations showed that five weeks after the end of exposure, PoF inhibited complex I activity of mice striatal mitochondria by 50%, and by 37% the one of cortical counterparts, resulting in a 25% and 15% decrease of the respiratory chain activity, respectively, thus indicating a greater sensibility of striatal versus cortical mitochondria complex I towards PoF (Fig. 3) [39].
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