The AAPS Journal

, Volume 14, Issue 4, pp 872–882

Pharmacokinetics and Tissue Disposition of Lenalidomide in Mice

  • Darlene M. Rozewski
  • Sarah E. M. Herman
  • William H. TownsII
  • 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
Research Article

DOI: 10.1208/s12248-012-9401-2

Cite this article as:
Rozewski, D.M., Herman, S.E.M., Towns, W.H. et al. AAPS J (2012) 14: 872. doi:10.1208/s12248-012-9401-2

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.

KEY WORDS

bioavailabilitydistributionlenalidomidemousepharmacokinetics

Copyright information

© American Association of Pharmaceutical Scientists 2012

Authors and Affiliations

  • Darlene M. Rozewski
    • 1
    • 2
  • Sarah E. M. Herman
    • 2
  • William H. TownsII
    • 2
  • Emilia Mahoney
    • 2
  • Matthew R. Stefanovski
    • 2
  • Jungook D. Shin
    • 2
  • Xiaoxia Yang
    • 1
  • Yue Gao
    • 1
  • Xiaobai Li
    • 3
  • David Jarjoura
    • 3
  • John C. Byrd
    • 2
    • 4
  • Amy J. Johnson
    • 2
    • 4
  • Mitch A. Phelps
    • 1
  1. 1.Division of PharmaceuticsCollege of PharmacyColumbusUSA
  2. 2.Division of HematologyDepartment of Internal MedicineColumbusUSA
  3. 3.Center for BiostatisticsThe Ohio State UniversityColumbusUSA
  4. 4.Division of Medicinal Chemistry, College of PharmacyThe Ohio State UniversityColumbusUSA