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Endogenous Coproporphyrin I and III are Altered in Multidrug Resistance-Associated Protein 2-Deficient (TR-) Rats.
Journal article

Endogenous Coproporphyrin I and III are Altered in Multidrug Resistance-Associated Protein 2-Deficient (TR-) Rats.

  • Bezençon J Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
  • Saran C Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA; Department of Pharmacology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Hussner J Biopharmacy, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
  • Beaudoin JJ Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
  • Zhang Y Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb Company, Princeton, NJ, USA.
  • Shen H Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb Company, Princeton, NJ, USA.
  • Fallon JK Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
  • Smith PC Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
  • Meyer Zu Schwabedissen HE Biopharmacy, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
  • Brouwer KLR Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA. Electronic address: kbrouwer@unc.edu.
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  • 2020-10-15
Published in:
  • Journal of pharmaceutical sciences. - 2020
Biomarker(s)
Disease effect(s)
Membrane transport
Multidrug resistance-associated protein(s) (MRP)
Organic anion transporting polypeptide(s) (OATP)
Proteomic
Transporter(s)
English Recent studies have focused on coproporphyrin (CP)-I and CP-III (CPs) as endogenous biomarkers for organic anion transporting polypeptides (OATPs). Previous data showed that CPs are also substrates of multidrug resistance-associated protein (MRP/Mrp) 2 and 3. This study was designed to examine the impact of loss of Mrp2 function on the routes of excretion of endogenous CPs in wild-type (WT) Wistar compared to Mrp2-deficient TR- rats. To exclude possible confounding effects of rat Oatps, the transport of CPs was investigated in Oatp-overexpressing HeLa cells. Results indicated that CPs are substrates of rodent Oatp1b2, and that CP-III is a substrate of Oatp2b1. Quantitative targeted absolute proteomic (QTAP) analysis revealed no differences in Oatps, but an expected significant increase in Mrp3 protein levels in TR- compared to WT rat livers. CP-I and CP-III concentrations measured by LC-MS/MS were elevated in TR- compared to WT rat liver, while CP-I and CP-III estimated biliary clearance was decreased 75- and 840-fold in TR- compared to WT rats, respectively. CP-III concentrations were decreased 14-fold in the feces of TR- compared to WT rats, but differences in CP-I were not significant. In summary, the disposition of CPs was markedly altered by loss of Mrp2 and increased Mrp3 function as measured in TR- rats.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/139256
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