Document Detail


Combination lopinavir and ritonavir alter exogenous and endogenous bile acid disposition in sandwich-cultured rat hepatocytes.
MedLine Citation:
PMID:  23091188     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Inhibition of the bile salt export pump (BSEP) can cause intracellular accumulation of bile acids and is a risk factor for drug-induced liver injury in humans. Antiretroviral protease inhibitors lopinavir (LPV) and ritonavir (RTV) are reported BSEP inhibitors. However, the consequences of LPV and RTV, alone and combined (LPV/r), on hepatocyte viability, bile acid transport, and endogenous bile acid disposition in rat hepatocytes have not been examined. The effect of LPV, RTV, and LPV/r on cellular viability and the disposition of [(3)H]taurocholic acid (TCA) and [(14)C]chenodeoxycholic acid (CDCA) was determined in sandwich-cultured rat hepatocytes (SCRH) and suspended rat hepatocytes. Lactate dehydrogenase and ATP assays revealed a concentration-dependent effect of LPV and RTV on cellular viability. LPV (5 µM), alone and combined with 5 µM RTV, significantly decreased [(3)H]TCA accumulation in cells + bile of SCRHs compared with control. LPV/r significantly increased [(3)H]TCA cellular accumulation (7.7 ± 0.1 pmol/mg of protein) compared with vehicle and 5 µM LPV alone (5.1 ± 0.7 and 5.0 ± 0.5 pmol/mg of protein). The [(3)H]TCA biliary clearance was reduced significantly by LPV and RTV and further reduced by LPV/r. LPV and RTV did not affect the initial uptake rates of [(3)H]TCA or [(14)C]CDCA in suspended rat hepatocytes. LPV (50 µM), RTV (5 µM), and LPV/r (5 and 50 µM/5 µM) significantly decreased the accumulation of total measured endogenous bile acids (TCA, glycocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, and α/β-tauromuricholic acid) in SCRH. Quantification of endogenous bile acids in SCRH may reveal important adaptive responses associated with exposure to known BSEP inhibitors.
Authors:
LaToya M Griffin; Paul B Watkins; Cassandra H Perry; Robert L St Claire; Kim L R Brouwer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-10-22
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  41     ISSN:  1521-009X     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-12-21     Completed Date:  2013-06-25     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  188-96     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Bile Acids and Salts / metabolism*
Carbon Radioisotopes / metabolism
Cell Survival / drug effects
Cells, Cultured
HIV Protease Inhibitors / administration & dosage,  pharmacology*
Hepatocytes / metabolism*
Lopinavir / administration & dosage,  pharmacology*
Rats
Ritonavir / administration & dosage,  pharmacology*
Grant Support
ID/Acronym/Agency:
R01 GM041935/GM/NIGMS NIH HHS; R01-GM41935/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Bile Acids and Salts; 0/Carbon Radioisotopes; 0/HIV Protease Inhibitors; 2494G1JF75/Lopinavir; O3J8G9O825/Ritonavir
Comments/Corrections

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