PT  - JOURNAL ARTICLE
AU  - Gardiner, Philip
AU  - Paine, Stuart W.
TI  - The Impact of Hepatic Uptake on the Pharmacokinetics of Organic Anions
AID  - 10.1124/dmd.111.039842
DP  - 2011 Oct 01
TA  - Drug Metabolism and Disposition
PG  - 1930--1938
VI  - 39
IP  - 10
4099  - http://dmd.aspetjournals.org/content/39/10/1930.short
4100  - http://dmd.aspetjournals.org/content/39/10/1930.full
SO  - Drug Metab Dispos2011 Oct 01; 39
AB  - The disposition of seven marketed and two AstraZeneca acid (organic anion) compounds with a range of volume of distribution at steady state (Vss) and clearance have been profiled in rat and dog. Pharmacokinetic (PK) parameters along with liver and muscle tissue levels were collected, and their contributions 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 the in vitro hepatocyte assay that monitors loss of compound from the incubation media along with physiologically based PK (PBPK) modeling 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 with 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, because of 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 interspecies differences in liver uptake. In this situation, the potential use of human hepatocytes combined with PBPK modeling avoids the question of which species pharmacokinetics is most predictive to humans.