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Research ArticleArticle

The Impact of Solute Carrier (SLC) Drug Uptake Transporter Loss in Human and Rat Cryopreserved Hepatocytes on Clearance Predictions

Patrik Lundquist, Johan Lööf, Anna-Karin Sohlenius-Sternbeck, Eva Floby, Jenny Johansson, Johan Bylund, Janet Hoogstraate, Lovisa Afzelius and Tommy B. Andersson
Drug Metabolism and Disposition March 2014, 42 (3) 469-480; DOI: https://doi.org/10.1124/dmd.113.054676
Patrik Lundquist
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje, (P.L., J.L., A.-K.S.-S., E.F., J.J., J.B., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal, (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala, (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, (T.B.A.), Sweden
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Johan Lööf
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje, (P.L., J.L., A.-K.S.-S., E.F., J.J., J.B., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal, (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala, (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, (T.B.A.), Sweden
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Anna-Karin Sohlenius-Sternbeck
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje, (P.L., J.L., A.-K.S.-S., E.F., J.J., J.B., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal, (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala, (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, (T.B.A.), Sweden
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Eva Floby
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje, (P.L., J.L., A.-K.S.-S., E.F., J.J., J.B., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal, (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala, (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, (T.B.A.), Sweden
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Jenny Johansson
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje, (P.L., J.L., A.-K.S.-S., E.F., J.J., J.B., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal, (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala, (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, (T.B.A.), Sweden
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Johan Bylund
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje, (P.L., J.L., A.-K.S.-S., E.F., J.J., J.B., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal, (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala, (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, (T.B.A.), Sweden
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Janet Hoogstraate
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje, (P.L., J.L., A.-K.S.-S., E.F., J.J., J.B., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal, (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala, (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, (T.B.A.), Sweden
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Lovisa Afzelius
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje, (P.L., J.L., A.-K.S.-S., E.F., J.J., J.B., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal, (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala, (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, (T.B.A.), Sweden
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Tommy B. Andersson
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje, (P.L., J.L., A.-K.S.-S., E.F., J.J., J.B., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal, (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala, (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, (T.B.A.), Sweden
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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 [human Na+-taurocholate cotransporting polypeptide (NTCP), human organic anion transporting polypeptides (OATPs), human organic anion transporters, and human organic cation transporters (OCTs)] was considerably reduced compared with 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 human OATP1B1 and OATP1B3 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 with 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 with 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 underpredictions of in vivo metabolic clearance from cryopreserved hepatocytes.

Footnotes

    • Received October 2, 2013.
    • Accepted January 6, 2014.
  • dx.doi.org/10.1124/dmd.113.054676.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (3)
Drug Metabolism and Disposition
Vol. 42, Issue 3
1 Mar 2014
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Research ArticleArticle

Drug Uptake Transporters in Cryopreserved Hepatocytes

Patrik Lundquist, Johan Lööf, Anna-Karin Sohlenius-Sternbeck, Eva Floby, Jenny Johansson, Johan Bylund, Janet Hoogstraate, Lovisa Afzelius and Tommy B. Andersson
Drug Metabolism and Disposition March 1, 2014, 42 (3) 469-480; DOI: https://doi.org/10.1124/dmd.113.054676

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Research ArticleArticle

Drug Uptake Transporters in Cryopreserved Hepatocytes

Patrik Lundquist, Johan Lööf, Anna-Karin Sohlenius-Sternbeck, Eva Floby, Jenny Johansson, Johan Bylund, Janet Hoogstraate, Lovisa Afzelius and Tommy B. Andersson
Drug Metabolism and Disposition March 1, 2014, 42 (3) 469-480; DOI: https://doi.org/10.1124/dmd.113.054676
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