Association of pharmacokinetic profiles of lenalidomide in human plasma simulated using pharmacokinetic data in humanized-liver mice with liver toxicity detected by human serum albumin RNA

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  • Murayama Norie
    Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University
  • Suemizu Hiroshi
    Central Institute for Experimental Animals
  • Uehara Shotaro
    Central Institute for Experimental Animals
  • Kusama Takashi
    Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University
  • Mitsui Marina
    Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University
  • Kamiya Yusuke
    Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University
  • Shimizu Makiko
    Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University
  • Guengerich F. Peter
    Department of Biochemistry, Vanderbilt University School of Medicine, USA
  • Yamazaki Hiroshi
    Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University

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Abstract

<p>Lenalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species. Screening for thalidomide analogs devoid of teratogenicity/toxicity—attributable to drug metabolism and disposition, but having immunomodulatory properties—is a strategic pathway towards development of new anticancer drugs. Plasma concentrations of lenalidomide were investigated in immunodeficient control and humanized-liver mice following oral administration of lenalidomide (50 mg/kg). Plasma concentrations of lenalidomide (1-2 hr after administration) were slightly but significantly higher in humanized-liver mice than in control mice (p < 0.05). Human albumin mRNA, a liver-specific toxicity marker, was found in the blood of humanized-liver mice 24 hr after lenalidomide administration. Simulations of human plasma concentrations of lenalidomide were achieved with simplified physiologically-based pharmacokinetic models in control and humanized-liver mice or by the direct fitting analysis of reported human data, in accordance with reported lenalidomide concentrations after low dose administration in humans. The results indicate that pharmacokinetic profiles of lenalidomide, a compound resulting from introducing one aromatic amino group into thalidomide and removing one keto group, resulted in less species variation in in vivo pharmacokinetics in control and humanized-liver mice and that immunodeficient humanized-liver mice can serve as experimental model animals for human liver injury in drug development at high doses, with human albumin RNA analysis in plasma.</p>

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