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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• 作者：Sayako Nishiyama ; Hiroshi Suemizu ; Norio Shibata ; F. Peter Guengerich ; Hiroshi Yamazaki
• 刊名：Chemical Research in Toxicology
• 出版年：2015
• 出版时间：November 16, 2015
• 年：2015
• 卷：28
• 期：11
• 页码：2088-2090
• 全文大小：212K
• ISSN：1520-5010

文摘

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 鈥渉umanized鈥?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.