RT Journal Article
SR Electronic
T1 Prediction of the Pharmacokinetics of Atorvastatin, Cerivastatin, and Indomethacin Using Kinetic Models Applied to Isolated Rat Hepatocytes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1365
OP 1374
DO 10.1124/dmd.107.019455
VO 36
IS 7
A1 Stuart W. Paine
A1 Alison J. Parker
A1 Philip Gardiner
A1 Peter J. H. Webborn
A1 Robert J. Riley
YR 2008
UL http://dmd.aspetjournals.org/content/36/7/1365.abstract
AB The disposition of atorvastatin, cerivastatin, and indomethacin, established substrates of rat hepatic basolateral uptake transporters, has been evaluated in suspended rat hepatocytes. Cell and media concentration-time data were simultaneously fitted to a model incorporating active uptake, permeation, binding, and metabolism. Use of the model to estimate the ratio of intracellular to extracellular steady-state free drug concentrations demonstrated the strong influence of active uptake on the kinetics of atorvastatin (18:1) and cerivastatin (8:1), in comparison with indomethacin (3.5:1). Indomethacin, however, was shown to have a higher uptake clearance (599 ± 101 μl/min/106 cells) than atorvastatin (375 ± 45 μl/min/106 cells) and cerivastatin (413 ± 47 μl/min/106 cells). The high passive permeability of indomethacin (237 ± 63 μl/min/106 cells) clearly negated the effect of the active transport on the overall disposition. An analogous physiological model was constructed that allowed prediction of the in vivo pharmacokinetics, including the free intracellular concentration in liver. Hepatic clearance was well predicted by the model, in contrast to predictions based on standard methods. Volume of distribution was well predicted for indomethacin and predicted reasonably for atorvastatin and cerivastatin and higher than might be expected for an acid compound. Furthermore, the terminal half-life predictions for all three compounds were within 2-fold of the observed values. The ability to estimate the free-intracellular hepatic concentration of uptake substrates has major benefits in terms of predicting pharmacokinetics, potential CYP-mediated drug-drug interactions, and efficacy of hepatically targeted therapeutics. The American Society for Pharmacology and Experimental Therapeutics