title: Metabolic profiles of pomalidomide in human plasma simulated with pharmacokinetic data in control and humanized-liver mice.
abstract: 1. Pomalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species such as rabbits. Screening for thalidomide analogs devoid of teratogenicity/toxicity - attributable to metabolites formed by cytochrome P450 enzymes - but having immunomodulatory properties is a strategic pathway towards development of new anticancer drugs. 2. In this study, plasma concentrations of pomalidomide, its primary 5-hydroxylated metabolite, and its glucuronide conjugate(s) were investigated in control and humanized-liver mice. Following oral administration of pomalidomide (100 mg/kg), plasma concentrations of 7-hydroxypomalidomide and 5-hydroxypomalidomide glucuronide were slightly higher in humanized-liver mice than in control mice. 3. Simulations of human plasma concentrations of pomalidomide were achieved with simplified physiologically-based pharmacokinetic models in both groups of mice in accordance with reported pomalidomide concentrations after low dose administration in humans. 4. The results indicate that pharmacokinetic profiles of pomalidomide were roughly similar between control mice and humanized-liver mice and that control and humanized-liver mice mediated pomalidomide 5-hydroxylation in vivo. Introducing one aromatic amino group into thalidomide resulted in less species differences in in vivo pharmacokinetics in control and humanized-liver mice.
authors.affiliation: a Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Tokyo , Japan.
authors.forename: Makiko
authors.identifier: http://orcid.org/0000-0002-3706-2454
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: b Central Institute for Experimental Animals , Kawasaki , Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suemizu
authors.affiliation: a Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Tokyo , Japan.
authors.forename: Marina
authors.initials: M
authors.lastname: Mitsui
authors.affiliation: c Graduate School of Engineering, Nagoya Institute of Technology , Nagoya , Japan , and.
authors.forename: Norio
authors.initials: N
authors.lastname: Shibata
authors.affiliation: d Department of Biochemistry , Vanderbilt University School of Medicine , Nashville , TN , United States.
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
authors.affiliation: a Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Tokyo , Japan.
authors.forename: Hiroshi
authors.identifier: http://orcid.org/0000-0002-1068-4261
authors.initials: H
authors.lastname: Yamazaki
mesh_terms: D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D020719:Glucuronides / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D055442:Metabolome; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D020719:Glucuronides; D013792:Thalidomide; D003577:Cytochrome P-450 Enzyme System; C467566:pomalidomide
keywords: PBPK modeling; TK-NOG mice; pomalidomide