title: The impact of hepatic uptake on the pharmacokinetics of organic anions.
abstract: The disposition of seven marketed and two AstraZeneca acid (organic anion) compounds with a range of volume of distribution at steady state (V(ss)) 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 V(ss) were calculated. The physiologically based prediction of V(ss) correlated (all predictions within 2-fold) with the V(ss) obtained from plasma PK analysis. The V(ss) 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 V(ss). 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 V(ss) 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 V(ss), 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.
authors.affiliation: Department of Discovery Drug Metabolism and Pharmacokinetics, AstraZeneca R&D Charnwood, Loughborough, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Gardiner
authors.forename: Stuart W
authors.initials: SW
authors.lastname: Paine
mesh_terms: D000818:Animals; D000838:Anions / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000493:pharmacokinetics; D001565:Benzoates / Q000493:pharmacokinetics; D001652:Bile Ducts / Q000378:metabolism; D004285:Dogs; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007213:Indomethacin / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D019808:Losartan / Q000493:pharmacokinetics; D008297:Male; D008954:Models, Biological; D009132:Muscles / Q000378:metabolism; D009930:Organic Chemicals / Q000493:pharmacokinetics*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013444:Sulfisoxazole / Q000493:pharmacokinetics; D000077333:Telmisartan; D014046:Tolmetin / Q000493:pharmacokinetics
chemical_list: D000838:Anions; D001562:Benzimidazoles; D001565:Benzoates; D009930:Organic Chemicals; D004364:Pharmaceutical Preparations; D013444:Sulfisoxazole; D014046:Tolmetin; D019808:Losartan; D000077333:Telmisartan; D007213:Indomethacin