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Research ArticleArticle

Major Loss of Solute Carrier (SLC) - Super Family Drug Uptake Transporters in Human and Rat Cryopreserved Hepatocytes

Patrik Lundquist, Johan Loof, Anna-Karin Sohlenius-Sternbeck, Eva Floby, Jenny Johansson, Johan Bylund, Janet Hoogstraate, Lovisa Afzelius and Tommy B. Andersson
Drug Metabolism and Disposition January 6, 2014, dmd.113.054676; DOI: https://doi.org/10.1124/dmd.113.054676
Patrik Lundquist
1 AstraZeneca/Uppsala University;
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Johan Loof
2 AstraZeneca;
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Anna-Karin Sohlenius-Sternbeck
2 AstraZeneca;
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Eva Floby
2 AstraZeneca;
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Jenny Johansson
2 AstraZeneca;
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Johan Bylund
3 AstraZeneca R&D Innovative Medicines;
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Janet Hoogstraate
2 AstraZeneca;
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Lovisa Afzelius
2 AstraZeneca;
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Tommy B. Andersson
4 Astra Zeneca Research and Development MoIndal
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  • For correspondence: tommy.b.andersson@astrazeneca.com
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Abstract

Cryopreserved hepatocytes are often used as a convenient tool in studies of hepatic drug metabolism and disposition. In this study the expression and activity of drug transporters in human and rat fresh and cryopreserved hepatocytes was investigated. In human cryopreserved hepatocytes Western blot analysis indicated that protein expression of the drug uptake transporters (hNTCP, hOATPs, hOATs and hOCTs) was considerably reduced compared to liver tissue. In rat cryopreserved cells the same trend was observed but to a lesser extent. Several rat transporters were reduced as a result of both isolation and cryopreservation procedures. Immunofluorescence showed that a large portion of remaining hOATP1B1 and hOATP1B3 transporters were internalized in human cryopreserved hepatocytes. Measuring uptake activity using known substrates of OATPs, OCTs and NTCP showed decreased activity in cryopreserved as compared to fresh hepatocytes in both species. The reduced uptake in cryopreserved hepatocytes limited the in vitro metabolism of several AstraZeneca compounds. A retrospective analysis of clearance predictions of AstraZeneca compounds suggested systematic lower clearance predicted using metabolic stability data from human cryopreserved hepatocytes compared to human liver microsomes. This observation is consistent with a loss of drug uptake transporters in cryopreserved hepatocytes. In contrast the predicted metabolic clearance from fresh rat hepatocytes was consistently higher than those predicted from liver microsomes consistent with retention of uptake transporters. The uptake transporters, which are decreased in cryopreserved hepatocytes, may be rate limiting for the metabolism of the compounds and thus be one explanation for under-predictions of in vivo metabolic clearance from cryopreserved hepatocytes.

  • active transport
  • drug transport
  • hepatic transport
  • hepatic uptake
  • hepatobiliary transport
  • hepatocytes
  • human pharmacokinetics
  • in vitro-in vivo scaling
  • isolated hepatocytes
  • transporters
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 51 (12)
Drug Metabolism and Disposition
Vol. 51, Issue 12
1 Dec 2023
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Research ArticleArticle

Major Loss of Solute Carrier (SLC) - Super Family Drug Uptake Transporters in Human and Rat Cryopreserved Hepatocytes

Patrik Lundquist, Johan Loof, Anna-Karin Sohlenius-Sternbeck, Eva Floby, Jenny Johansson, Johan Bylund, Janet Hoogstraate, Lovisa Afzelius and Tommy B. Andersson
Drug Metabolism and Disposition January 6, 2014, dmd.113.054676; DOI: https://doi.org/10.1124/dmd.113.054676

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Research ArticleArticle

Major Loss of Solute Carrier (SLC) - Super Family Drug Uptake Transporters in Human and Rat Cryopreserved Hepatocytes

Patrik Lundquist, Johan Loof, Anna-Karin Sohlenius-Sternbeck, Eva Floby, Jenny Johansson, Johan Bylund, Janet Hoogstraate, Lovisa Afzelius and Tommy B. Andersson
Drug Metabolism and Disposition January 6, 2014, dmd.113.054676; DOI: https://doi.org/10.1124/dmd.113.054676
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