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Simulation of Human Plasma Concentrations of Thalidomide and Primary 5-Hydroxylated Metabolites Explored with Pharmacokinetic Data in Humanized TK-NOG Mice.

Nishiyama S, Suemizu H, Shibata N, Guengerich FP, Yamazaki H
Chem Res Toxicol. 2015 28 (11): 2088-90

PMID: 26492539 · PMCID: PMC6345571 · DOI:10.1021/acs.chemrestox.5b00381

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 P450 3A5*1. 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 in vivo activation can be estimated for the first time.

MeSH Terms (10)

Animals Cytochrome P-450 CYP3A Glutathione Hepatocytes Humans Hydroxylation Liver Mice Teratogens Thalidomide

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