Novel in vitro-in vivo Extrapolation (IVIVE) Method to Predict Hepatic Organ Clearance in Rat
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Umehara, Ken-Ichi and Camenisch, Gian P. (2011) Novel in vitro-in vivo Extrapolation (IVIVE) Method to Predict Hepatic Organ Clearance in Rat. Pharmaceutical Research. ISSN 0724-8741
Abstract
Purpose. Drug elimination in the liver consists of uptake, metabolism, biliary excretion, and sinusoidal efflux from the hepatocytes to the blood. The purpose of our study was 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 (r2=0.928) as compared to parameter analysis using hepatocyte uptake only (r2=0.600), microsomal metabolism only (r2=0.687) or overall hepatobiliary excretion in sandwich-cultured hepatocytes (r2=0.321).
Conclusions. The present analysis is a new attempt to predict hepatic elimination under consideration of multiple clearance processes. The in vivo hepatic clearances of 13 compounds in rats were well predicted using an IVIVE analysis method based on in vitro assays.
| Item Type: | Article |
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| Additional Information: | The present manuscript has been already accepted by the journal, followed by the proof reading process. |
| Keywords: | Suspended and sandwich-cultured hepatocytes; hepatic uptake; biliary excretion; sinusoidal efflux; prediction |
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| Date Deposited: | 13 Oct 2015 13:15 |
| Last Modified: | 13 Oct 2015 13:15 |
| URI: | https://oak.novartis.com/id/eprint/4082 |