A physiologically based toxicokinetic modelling approach to predict relevant concentrations for in vitro testing.
Our study was performed in the context of an in vitro primary hepatic cell culture as an alternative for the in vivo cancerogenic bioassay. The 29 substances which are to be used in the in vitro primary hepatic cell culture have been tested in 2-year bioassays and a 14-day short term study. The aim of this modelling study was to simulate the concentration--time profile of the compounds when given by the oral route at the doses tested in the previous studies taking into account the percentage of the dose absorbed. The model contained seven tissue compartments with uptake from the gastrointestinal tract into the portal vein. Because the primary hepatic cell culture is metabolically competent and the primary interest was to model the concentration in the portal vein, the hepatic vein and the systemic circulation (blood) in the beginning we did not include elimination. Partitioning between blood and tissues was calculated according to a published biologically based algorithm. The substances' kinetic profile differed according to their blood: tissue partitioning. Maximal concentrations in portal vein, hepatic vein and the blood depended mainly on the dose and the fraction absorbed which were the most critical parameters in this respect. Our study demonstrates an application of BPTK modelling for the purpose to simulate concentrations for planning the doses for an in vitro study. BPTK modelling seems to be a better approach than using data from in vitro studies on cytotoxicity.
Federal Institute for Risk Assessment, Thielallee 88-92, 14195, Berlin, Germany. hans.mielke@bfr.bund.de
Hans
H
Mielke
Lennart T
LT
Anger
Markus
M
Schug
Jan G
JG
Hengstler
Ralf
R
Stahlmann
Ursula
U
Gundert-Remy
D000826:Animal Testing Alternatives; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001711:Biotransformation; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D002478:Cells, Cultured; D055598:Chemical Phenomena; D003198:Computer Simulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009153:Mutagens / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D009994:Osmolar Concentration; D010599:Pharmacokinetics; D051381:Rats; D014018:Tissue Distribution; D018675:Toxicity Tests / Q000379:methods / Q000592:standards
D015415:Biomarkers; D002273:Carcinogens; D009153:Mutagens