Pharmacokinetics and Tissue Disposition of Lenalidomide in Mice
Journal Title: The AAPS Journal - Year 2012, Vol 14, Issue 4
Abstract
Lenalidomide is a synthetic derivative of thalidomide exhibiting multiple immunomodulatory activities beneficial in the treatment of several hematological malignancies. Murine pharmacokinetic characterization necessary for translational and further preclinical investigations has not been published. Studies herein define mouse plasma pharmacokinetics and tissue distribution after intravenous (IV) bolus administration and bioavailability after oral and intraperitoneal delivery. Range finding studies used lenalidomide concentrations up to 15 mg/kg IV, 22.5 mg/kg intraperitoneal injections (IP), and 45 mg/kg oral gavage (PO). Pharmacokinetic studies evaluated doses of 0.5, 1.5, 5, and 10 mg/kg IV and 0.5 and 10 mg/kg doses for IP and oral routes. Liquid chromatography–tandem mass spectrometry was used to quantify lenalidomide in plasma, brain, lung, liver, heart, kidney, spleen, and muscle. Pharmacokinetic parameters were estimated using noncompartmental and compartmental methods. Doses of 15 mg/kg IV, 22.5 mg/kg IP, and 45 mg/kg PO lenalidomide caused no observable toxicity up to 24 h postdose. We observed dose-dependent kinetics over the evaluated dosing range. Administration of 0.5 and 10 mg/kg resulted in systemic bioavailability ranges of 90–105% and 60–75% via IP and oral routes, respectively. Lenalidomide was detectable in the brain only after IV dosing of 5 and 10 mg/kg. Dose-dependent distribution was also observed in some tissues. High oral bioavailability of lenalidomide in mice is consistent with oral bioavailability in humans. Atypical lenalidomide tissue distribution was observed in spleen and brain. The observed dose-dependent pharmacokinetics should be taken into consideration in translational and preclinical mouse studies.
Authors and Affiliations
Darlene M. Rozewski, Sarah E. M. Herman, William H. Towns, II, Emilia Mahoney, Matthew R. Stefanovski, Jungook D. Shin, Xiaoxia Yang, Yue Gao, Xiaobai Li, David Jarjoura, John C. Byrd, Amy J. Johnson, Mitch A. Phelps
Keywords
Related Articles
- EP ID EP681263
- DOI 10.1208/s12248-012-9401-2
- Views 79
- Downloads 0
Erratum to: Modeling the Effects of Vaccination and Treatment on Pandemic Influenza
The online version of the original article can be found at 10.1208/s12248-011-9284-7.
Brain tissue lipidomics: Direct probing using matrix-assisted laser desorption/ionization mass spectrometry
Lipidomics is the new frontier in biomolecular structural studies. Not only are lipids the main components in membranes that define the contours of the cell and its organelles, but they are also used for storage. Lipids...
The joint food and agriculture organization of the united nations/world health organization expert committee on food additives and its role in the evaluation of the safety of veterinary drug residues in foods
The Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) recommended the evaluation of food additives at the international level through the establishment of an expert com...
Futility Rules in Bioequivalence Trials with Sequential Designs
The online version of this article (doi:10.1208/s12248-013-9540-0) contains supplementary material, which is available to authorized users.
Triple Recycling Processes Impact Systemic and Local Bioavailability of Orally Administered Flavonoids
The online version of this article (doi:10.1208/s12248-015-9732-x) contains supplementary material, which is available to authorized users.