Use of mechanistic modeling to assess interindividual variability and interspecies differences in active uptake in human and rat hepatocytes

Karelle Ménochet, Kathryn E. Kenworthy, J. Brian Houston, Aleksandra Galetin

    Research output: Contribution to journalArticlepeer-review


    Interindividual variability in activity of uptake transporters is evident in vivo, yet limited data exist in vitro, confounding in vitro-in vivo extrapolation. The uptake kinetics of seven organic aniontransporting polypeptide substrates was investigated over a concentration range in plated cryopreserved human hepatocytes. Active uptake clearance (CL active, u), bidirectional passive diffusion (Pdiff), intracellular binding, and metabolism were estimated for bosentan, pitavastatin, pravastatin, repaglinide, rosuvastatin, telmisartan, and valsartan in HU4122 donor using a mechanistic two-compartment model in Matlab. Full uptake kinetics of rosuvastatin and repaglinide were also characterized in two additional donors, whereas for the remaining drugs CLactive, u was estimated at a single concentration. The unbound affinity constant (Km, u) and Pdiff values were consistent across donors, whereas Vmax was on average up to 2.8-fold greater in donor HU4122. Consistency in Km, u values allowed extrapolation of single concentration uptake activity data and assessment of interindividual variability in CLactiveacross donors. The maximal contribution of active transport to total uptake differed among donors, for example, 85 to 96% and 68 to 87% for rosuvastatin and repaglinide, respectively; however, in all cases the active process was the major contributor. In vitro-in vivo extrapolation indicated a general underprediction of hepatic intrinsic clearance, an average empirical scaling factor of 17.1 was estimated on the basis of seven drugs investigated in three hepatocyte donors, and donor-specific differences in empirical factors are discussed. Uptake K m, u and CLactive, u were on average 4.3- and 7.1-fold lower in human hepatocytes compared with our previously published rat data. A strategy for the use of rat uptake data to facilitate the experimental design in human hepatocytes is discussed. Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics.
    Original languageEnglish
    Pages (from-to)1744-1756
    Number of pages12
    JournalDrug Metabolism and Disposition
    Issue number9
    Publication statusPublished - Sept 2012


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