Metabolic profiles of pomalidomide in human plasma simulated with pharmacokinetic data in control and humanized-liver mice
| Autor: | Makiko Shimizu, Hiroshi Yamazaki, Norio Shibata, Marina Mitsui, F. Peter Guengerich, Hiroshi Suemizu |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Health
Toxicology and Mutagenesis Metabolite Angiogenesis Inhibitors Pharmacology Toxicology 030226 pharmacology & pharmacy Biochemistry Article Mice 03 medical and health sciences chemistry.chemical_compound Glucuronides 0302 clinical medicine Cytochrome P-450 Enzyme System Pharmacokinetics Oral administration In vivo medicine Animals Humans Chemistry General Medicine Pomalidomide Thalidomide Liver 030220 oncology & carcinogenesis Toxicity Hepatocytes Metabolome Microsomes Liver Glucuronide medicine.drug |
| Zdroj: | Xenobiotica. 47:844-848 |
| ISSN: | 1366-5928 0049-8254 |
| DOI: | 10.1080/00498254.2016.1247218 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|