Human plasma concentrations of trimethylamine N-oxide extrapolated using pharmacokinetic modeling based on metabolic profiles of deuterium-labeled trimethylamine in humanized-liver mice

摘要

Medicinal carnitine-derived and dietary-derived malodorous trimethylamine and its non-malodorous metabolite trimethylamine N-oxide were historically regarded as nontoxic. Clinical and toxicological interest has recently arisen because of their potential association with atherosclerosis. We previously reported a human physiologically based pharmacokinetic (PBPK) model for trimethylamine and its primary metabolite, trimethylamine N-oxide, based on reported rat trimethylamine pharmacokinetics. However, rats are poor metabolizers with respect to trimethylamine N-oxygenation, and this species difference was investigated in vitro using substrate depletion rates in rat and human liver microsomes. The current study investigated the pharmacokinetics of deuterium-labeled trimethylamine orally administered to immunodeficient humanized-liver mice transplanted with commercially available human hepatocytes. Trimethylamine N-oxide was extensively formed in vivo in humanized-liver mice, but not in control mice. The experimental pharmacokinetic data of deuterium-labeled trimethylamine and its N-oxide in humanized-liver mice were scaled up for application to a human PBPK model. The human plasma concentration curves generated by the resulting simple PBPK model were consistent with concentrations in humans reported in the literature. The model can also simulate human plasma levels of trimethylamine and trimethylamine N-oxide during treatment with the prescription medicine L-carnitine and in trimethylamine loading tests. The predicted plasma levels were in the ranges that occur under the consumption of daily dietary foodstuff; such levels are associated with few toxicological impacts. The present PBPK model for trimethylamine and trimethylamine N-oxide could estimate daily doses by both forward and reverse dosimetry and could facilitate risk assessment in humans.