Abstract
The disposition of 7 marketed and 2 AstraZeneca acid (organic anion) compounds with a range of Vss and clearance have been profiled in rat and dog. PK parameters along with liver and muscle tissue levels were collected and their contribution to total Vss were calculated. The physiologically based prediction of Vss correlated (all predictions within 2-fold) with the Vss obtained from plasma PK analysis. The Vss of the acid drugs with atypically high values could be explained by significant sequestering of compound to the liver. A 'media loss' in vitro hepatocyte assay that monitors loss of compound from the incubation media along with PBPK modelling was assessed for its ability to accurately predict the impact of hepatic uptake on both clearance and Vss. This methodology significantly improved the prediction of metabolic in vivo clearance compared to standard hepatocyte scaling approaches that do not take into account hepatic uptake. Predictions of Vss from the "media loss" assay also correlate with the measured values from plasma PK analysis. However, hepatic uptake will have little overall impact on half-life, due to the concomitant impact on both Cl and Vss, as long as hepatic extraction is not high. The methodology described here is particularly useful when there is no allometric relationship between species as a result of inter-species differences in liver uptake. In this situation, the potential use of human hepatocytes combined with PBPK modelling avoids the question of which species PK is most predictive to man.
- active transport
- drug disposition
- hepatobiliary transport
- hepatocytes
- in vitro-in vivo prediction
- isolated hepatocytes
- pharmacokinetic modeling
- physiologically-based modeling
- Received March 31, 2011.
- Accepted July 21, 2011.
- The American Society for Pharmacology and Experimental Therapeutics