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Research ArticleArticle

Combination Lopinavir and Ritonavir Alter Exogenous and Endogenous Bile Acid Disposition in Sandwich-Cultured Rat Hepatocytes

LaToya M. Griffin, Paul B. Watkins, Cassandra H. Perry, Robert L. St. Claire III and Kim L. R. Brouwer
Drug Metabolism and Disposition January 2013, 41 (1) 188-196; DOI: https://doi.org/10.1124/dmd.112.047225
LaToya M. Griffin
UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (L.M.G., P.B.W., K.L.R.B.); Hamner-University of North Carolina, Institute for Drug Safety Sciences, Research Triangle Park, North Carolina (P.B.W.); and Qualyst Transporter Solutions, Durham, North Carolina (C.H.P., R.L.S.)
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Paul B. Watkins
UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (L.M.G., P.B.W., K.L.R.B.); Hamner-University of North Carolina, Institute for Drug Safety Sciences, Research Triangle Park, North Carolina (P.B.W.); and Qualyst Transporter Solutions, Durham, North Carolina (C.H.P., R.L.S.)
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Cassandra H. Perry
UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (L.M.G., P.B.W., K.L.R.B.); Hamner-University of North Carolina, Institute for Drug Safety Sciences, Research Triangle Park, North Carolina (P.B.W.); and Qualyst Transporter Solutions, Durham, North Carolina (C.H.P., R.L.S.)
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Robert L. St. Claire III
UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (L.M.G., P.B.W., K.L.R.B.); Hamner-University of North Carolina, Institute for Drug Safety Sciences, Research Triangle Park, North Carolina (P.B.W.); and Qualyst Transporter Solutions, Durham, North Carolina (C.H.P., R.L.S.)
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Kim L. R. Brouwer
UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (L.M.G., P.B.W., K.L.R.B.); Hamner-University of North Carolina, Institute for Drug Safety Sciences, Research Triangle Park, North Carolina (P.B.W.); and Qualyst Transporter Solutions, Durham, North Carolina (C.H.P., R.L.S.)
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Abstract

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 [3H]taurocholic acid (TCA) and [14C]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 [3H]TCA accumulation in cells + bile of SCRHs compared with control. LPV/r significantly increased [3H]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 [3H]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 [3H]TCA or [14C]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.

Footnotes

  • This work was supported by the National Institutes of Health [Grant R01-GM41935].

  • dx.doi.org/10.1124/dmd.112.047225.

  • Received June 14, 2012.
  • Accepted October 22, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (1)
Drug Metabolism and Disposition
Vol. 41, Issue 1
1 Jan 2013
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Research ArticleArticle

Protease Inhibitors Alter Bile Acid Transport

LaToya M. Griffin, Paul B. Watkins, Cassandra H. Perry, Robert L. St. Claire and Kim L. R. Brouwer
Drug Metabolism and Disposition January 1, 2013, 41 (1) 188-196; DOI: https://doi.org/10.1124/dmd.112.047225

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Research ArticleArticle

Protease Inhibitors Alter Bile Acid Transport

LaToya M. Griffin, Paul B. Watkins, Cassandra H. Perry, Robert L. St. Claire and Kim L. R. Brouwer
Drug Metabolism and Disposition January 1, 2013, 41 (1) 188-196; DOI: https://doi.org/10.1124/dmd.112.047225
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