title: Mechanistic Modeling of Pitavastatin Disposition in Sandwich-Cultured Human Hepatocytes: A Proteomics-Informed Bottom-Up Approach.
abstract: Isolated human hepatocytes are commonly used to predict transporter-mediated clearance in vivo. Such predictions, however, do not provide estimations of transporter contributions and consequently do not allow predictions of the outcome resulting from a change in the activity of a certain transporter, for example, by inhibition or a genetic variant with reduced function. Pitavastatin is a drug that is heavily dependent on hepatic transporters for its elimination, and it is excreted mainly as unchanged drug in the bile. For this reason, pitavastatin was used as a model drug to demonstrate the applicability of a bottom-up approach to predict transporter-mediated disposition in sandwich-cultured human hepatocytes (SCHHs), allowing for the estimation of transporter contributions. Transport experiments in transfected human embryonic kidney cells (HEK293 cell lines) and inverted membrane vesicles overexpressing each of the relevant transport proteins were used to generate parameter estimates for the mechanistic model. By adjusting for differences in transporter abundance between the in vitro systems and individual SCHH batches, the model successfully predicted time profiles of medium and intracellular accumulation. Our predictions of pitavastatin bile accumulation could not be confirmed, however, because of a very low biliary excretion of pitavastatin in relation to the hepatic uptake in our SCHHs. This study is, to our knowledge, the first to successfully simulate transporter-mediated processes in a complex system such as SCHHs at the level of individual transport proteins using a bottom-up approach.
authors: Department of Pharmacy (A.V., A.M., E.K.K., M.K., P.A.), Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University (M.C.K.), and Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium, Science for Life Laboratory (P.A.), Uppsala, Sweden; and Bristol-Myers Squibb, Princeton, New Jersey (Y.L.).
authors: Anna
authors: A
authors: Vildhede
authors: Department of Pharmacy (A.V., A.M., E.K.K., M.K., P.A.), Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University (M.C.K.), and Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium, Science for Life Laboratory (P.A.), Uppsala, Sweden; and Bristol-Myers Squibb, Princeton, New Jersey (Y.L.).
authors: André
authors: A
authors: Mateus
authors: Department of Pharmacy (A.V., A.M., E.K.K., M.K., P.A.), Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University (M.C.K.), and Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium, Science for Life Laboratory (P.A.), Uppsala, Sweden; and Bristol-Myers Squibb, Princeton, New Jersey (Y.L.).
authors: Elin K
authors: EK
authors: Khan
authors: Department of Pharmacy (A.V., A.M., E.K.K., M.K., P.A.), Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University (M.C.K.), and Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium, Science for Life Laboratory (P.A.), Uppsala, Sweden; and Bristol-Myers Squibb, Princeton, New Jersey (Y.L.).
authors: Yurong
authors: Y
authors: Lai
authors: Department of Pharmacy (A.V., A.M., E.K.K., M.K., P.A.), Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University (M.C.K.), and Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium, Science for Life Laboratory (P.A.), Uppsala, Sweden; and Bristol-Myers Squibb, Princeton, New Jersey (Y.L.).
authors: Maria
authors: M
authors: Karlgren
authors: Department of Pharmacy (A.V., A.M., E.K.K., M.K., P.A.), Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University (M.C.K.), and Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium, Science for Life Laboratory (P.A.), Uppsala, Sweden; and Bristol-Myers Squibb, Princeton, New Jersey (Y.L.).
authors: Per
authors: P
authors: Artursson
authors: Department of Pharmacy (A.V., A.M., E.K.K., M.K., P.A.), Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University (M.C.K.), and Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium, Science for Life Laboratory (P.A.), Uppsala, Sweden; and Bristol-Myers Squibb, Princeton, New Jersey (Y.L.).
authors: Maria C
authors: MC
authors: Kjellsson
mesh_terms: D000368:Aged; D001692:Biological Transport / Q000502:physiology; D018929:Cell Culture Techniques / Q000379:methods*; D005260:Female; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D040901:Proteomics / Q000379:methods*; D011804:Quinolines / Q000378:metabolism*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; C108475:pitavastatin