Abstract
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.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.039842.
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ABBREVIATIONS:
- PK
- pharmacokinetic(s)
- CL
- clearance
- Vd
- volume of distribution
- Vss
- volume of distribution at steady state
- PBPK
- physiologically based pharmacokinetics
- CLinc
- clearance from the incubation
- LC-MS/MS
- liquid chromatography/tandem mass spectrometry
- HPLC
- high-performance liquid chromatography
- CLmed
- clearance from the medium
- kmem
- proportionality constant between amount in membrane and concentration in medium
- CLint, met
- unbound metabolic intrinsic clearance
- fmed, ss
- fraction in the medium at steady state
- fuinc
- fraction unbound in the incubation
- CLint, L, pass
- liver unbound passive diffusion intrinsic clearance
- CLint, L, uptake
- liver unbound sinusoidal uptake intrinsic clearance
- CLint, L, efflux
- liver unbound sinusoidal efflux intrinsic clearance
- CLint, L
- liver unbound intrinsic clearance
- CLint, pass
- unbound passive diffusion intrinsic clearance
- CLint, efflux
- unbound sinusoidal efflux intrinsic clearance
- CLint, uptake
- unbound sinusoidal uptake intrinsic clearance
- kL, mem
- proportionality constant between free blood concentration and the amount of drug in the cell membranes of the liver.
- Received March 31, 2011.
- Accepted July 21, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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