Simulation of
Human Plasma Concentrations of Thalidomide
and Primary 5‑Hydroxylated Metabolites Explored with Pharmacokinetic
Data in Humanized TK-NOG Mice
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Abstract
Plasma
concentrations of thalidomide and primary 5-hydroxylated
metabolites including 5,6-dihydroxythalidomide and glutathione (GSH)
conjugate(s) were investigated in chimeric mice with highly “humanized”
liver cells harboring cytochrome <i>P450 3A5*1</i>. Following
oral administration of thalidomide (100 mg/kg), plasma concentrations
of GSH conjugate(s) of 5-hydroxythalidomide were higher in humanized
mice than in controls. Simulation of human plasma concentrations of
thalidomide were achieved with a simplified physiologically based
pharmacokinetic model in accordance with reported thalidomide concentrations.
The results indicate that the pharmacokinetics in humans of GSH conjugate
and/or catechol primary 5-hydroxylated thalidomide contributing <i>in vivo</i> activation can be estimated for the first time
