| Hepatic pharmacokinetics of cationic drugs in a high-fat emulsion induced rat model of non-alcoholic steatohepatitis. | |
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MedLine Citation:
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PMID: 21245286 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The hepatic pharmacokinetics of five selected cationic drugs (propranolol, labetalol, metoprolol, antipyrine and atenolol) was studied in the liver from control rats and from those with high-fat emulsion-induced non-alcoholic steatohepatitis (NASH). Studies were undertaken using an in situ perfused rat liver (IPRL) and multiple indicator dilution (MID), with outflow data being analysed with a physiologically-based organ pharmacokinetic model. Hepatic extraction was significantly lower in the NASH model with lipophilicity (logP(app)) being the main solute structural determinant of the observed differences in intrinsic elimination clearance (CL(int)) and permeability-surface area product (PS) with pK(a) defining the extent of sequestration in the liver (K(v)). The main pathophysiological determinants were liver fibrosis, leading to a decreased PS, liver fat causing an increase in K(v), and an increase in both total liver cytochrome P450 (CYP) concentration and CYP isoform expression for Cyp3a2 and Cyp2d2, causing an increase CL(int) in NASH rat livers compared to control livers. Changes in hepatic pharmacokinetics (PS, K(v), CL(int) and E) due to NASH were related to the physicochemical properties of drugs (logP(app) or pK(a)) and hepatic histopathological changes (FI, SI, and CYP concentration) by stepwise regression analysis. It thus appears that in NASH, counteracting mechanisms to facilitate hepatic removal are created in that NASH induced CYP expression facilitates hepatic drug extraction whereas NASH induced fibrosis and steatohepatitis inhibits hepatic extraction by decreasing hepatocyte permeability through fibrosis and hepatic sequestration. |
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Authors:
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Peng Li; Thomas A Robertson; Camilla A Thorling; Qian Zhang; Linda Fletcher; Darrell H G Crawford; Michael S Roberts |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-1-18 |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: - ISSN: 1521-009X ISO Abbreviation: - Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2011-1-19 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1 The University of Queensland; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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