| Novel In Vitro-In Vivo Extrapolation (IVIVE) Method to Predict Hepatic Organ Clearance in Rat. | |
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MedLine Citation:
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PMID: 22011931 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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PURPOSE: 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. |
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Authors:
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Ken-Ichi Umehara; Gian Camenisch |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-10-20 |
Journal Detail:
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Title: Pharmaceutical research Volume: - ISSN: 1573-904X ISO Abbreviation: - Publication Date: 2011 Oct |
Date Detail:
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Created Date: 2011-10-20 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8406521 Medline TA: Pharm Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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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. |
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