Simulation of Human Plasma Concentrations of Thalidomide and Primary 5-Hydroxylated Metabolites Explored with Pharmacokinetic Data in Humanized TK-NOG Mice.
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.
Showa Pharmaceutical University , Machida, Tokyo 194-8543, Japan.
Sayako
S
Nishiyama
Central Institute for Experimental Animals , Kawasaki-ku, Kawasaki 210-0821, Japan.
Hiroshi
H
Suemizu
Graduate School of Engineering, Nagoya Institute of Technology , Showa-ku, Nagoya 466-8555, Japan.
Norio
N
Shibata
Department of Biochemistry, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-0146, United States.
F Peter
FP
Guengerich
Showa Pharmaceutical University , Machida, Tokyo 194-8543, Japan.
Hiroshi
H
Yamazaki
D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D008099:Liver / Q000378:metabolism; D051379:Mice; D013723:Teratogens / Q000493:pharmacokinetics; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics
D013723:Teratogens; D013792:Thalidomide; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D005978:Glutathione