Novel in vitro-in vivo extrapolation (IVIVE) method to predict hepatic organ clearance in rat.
OBJECTIVE
Drug elimination in the liver consists of uptake, metabolism, biliary excretion, and sinusoidal efflux from the hepatocytes to the blood. We aimed to establish an accurate prediction method for liver clearance in rats, considering these four elimination processes. In vitro assays were combined to achieve improved predictions.


METHODS
In vitro clearances for uptake, metabolism, biliary excretion and sinusoidal efflux were determined for 13 selected compounds with various physicochemical and pharmacokinetic properties. Suspended hepatocytes, liver microsomes and sandwich-cultured hepatocytes were evaluated as in vitro models. Based on the individual processes, in vivo hepatic clearance was calculated. Subsequently, the predicted clearances were compared with the corresponding in vivo values from literature.


RESULTS
Using this in vitro-in vivo extrapolation method good linear correlation was observed between predicted and reported clearances. Linear regression analysis revealed much improved prediction for the novel method (r(2) = 0.928) as compared to parameter analysis using hepatocyte uptake only (r(2) = 0.600), microsomal metabolism only (r(2) = 0.687) or overall hepatobiliary excretion in sandwich-cultured hepatocytes (r(2) = 0.321).


CONCLUSIONS
In this new attempt to predict hepatic elimination under consideration of multiple clearance processes, in vivo hepatic clearances of 13 compounds in rats were well predicted using an IVIVE analysis method based on in vitro assays.
Drug-Drug Interaction Section (DDI) Drug Metabolism and Pharmacokinetics (DMPK), Novartis Institutes of Biomedical Research (NIBR) Novartis Pharma AG,, WSJ-153.2.02., Novartis Campus, CH-4002, Basel, Switzerland. ken-ichi.umehara@novartis.com
Ken-ichi
K
Umehara
Gian
G
Camenisch
D000818:Animals; D001659:Biliary Tract / Q000378:metabolism; D002478:Cells, Cultured; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004364:Pharmaceutical Preparations