Prediction of the pharmacokinetics of atorvastatin, cerivastatin, and indomethacin using kinetic models applied to isolated rat hepatocytes.
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 microl/min/10(6) cells) than atorvastatin (375 +/- 45 microl/min/10(6) cells) and cerivastatin (413 +/- 47 microl/min/10(6) cells). The high passive permeability of indomethacin (237 +/- 63 microl/min/10(6) 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.
Paine
Stuart W
SW
Department of Discovery Drug Metabolism & Pharmacokinetics, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, United Kingdom. stuart.paine@astrazeneca.com
Parker
Alison J
AJ
Gardiner
Philip
P
Webborn
Peter J H
PJ
Riley
Robert J
RJ
D000818:Animals; D000069059:Atorvastatin; D022781:Hepatocytes / Q000378:metabolism*; D006538:Heptanoic Acids / Q000493:pharmacokinetics*; D007213:Indomethacin / Q000493:pharmacokinetics*; D008297:Male; D008954:Models, Biological; D011725:Pyridines / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D006538:Heptanoic Acids; D011725:Pyridines; D011758:Pyrroles; D000069059:Atorvastatin; C086276:cerivastatin; D007213:Indomethacin