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Research ArticleArticle

Functional ATP-Binding Cassette Drug Efflux Transporters in Isolated Human and Rat Hepatocytes Significantly Affect Assessment of Drug Disposition

Patrik Lundquist, Gunilla Englund, Cristine Skogastierna, Johan Lööf, Jenny Johansson, Janet Hoogstraate, Lovisa Afzelius and Tommy B. Andersson
Drug Metabolism and Disposition March 2014, 42 (3) 448-458; DOI: https://doi.org/10.1124/dmd.113.054528
Patrik Lundquist
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje, (P.L., G.E., C.S., J.L., J.J., J.H., L.A.); Cardiovascular and Gastrointestinal Innovative Medicines DMPK, AstraZeneca R&D, Mölndal, (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala, (P.L.); and Section of Pharmacogenetics, Departments of Physiology and Pharmacology, Karolinska Institutet, Stockholm, (T.B.A.), Sweden
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Gunilla Englund
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje, (P.L., G.E., C.S., J.L., J.J., J.H., L.A.); Cardiovascular and Gastrointestinal Innovative Medicines DMPK, AstraZeneca R&D, Mölndal, (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala, (P.L.); and Section of Pharmacogenetics, Departments of Physiology and Pharmacology, Karolinska Institutet, Stockholm, (T.B.A.), Sweden
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Cristine Skogastierna
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje, (P.L., G.E., C.S., J.L., J.J., J.H., L.A.); Cardiovascular and Gastrointestinal Innovative Medicines DMPK, AstraZeneca R&D, Mölndal, (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala, (P.L.); and Section of Pharmacogenetics, Departments 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., G.E., C.S., J.L., J.J., J.H., L.A.); Cardiovascular and Gastrointestinal Innovative Medicines DMPK, AstraZeneca R&D, Mölndal, (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala, (P.L.); and Section of Pharmacogenetics, Departments 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., G.E., C.S., J.L., J.J., J.H., L.A.); Cardiovascular and Gastrointestinal Innovative Medicines DMPK, AstraZeneca R&D, Mölndal, (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala, (P.L.); and Section of Pharmacogenetics, Departments 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., G.E., C.S., J.L., J.J., J.H., L.A.); Cardiovascular and Gastrointestinal Innovative Medicines DMPK, AstraZeneca R&D, Mölndal, (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala, (P.L.); and Section of Pharmacogenetics, Departments 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., G.E., C.S., J.L., J.J., J.H., L.A.); Cardiovascular and Gastrointestinal Innovative Medicines DMPK, AstraZeneca R&D, Mölndal, (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala, (P.L.); and Section of Pharmacogenetics, Departments 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., G.E., C.S., J.L., J.J., J.H., L.A.); Cardiovascular and Gastrointestinal Innovative Medicines DMPK, AstraZeneca R&D, Mölndal, (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala, (P.L.); and Section of Pharmacogenetics, Departments of Physiology and Pharmacology, Karolinska Institutet, Stockholm, (T.B.A.), Sweden
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Abstract

Freshly isolated hepatocytes are considered the gold standard for in vitro studies of hepatic drug disposition. To ensure a reliable supply of cells, cryopreserved human hepatocytes are often used. ABC-superfamily drug efflux transporters are key elements in hepatic drug disposition. These transporters are often considered lost after isolation of hepatocytes. In the present study, the expression and activity of ABC transporters BCRP, BSEP, P-gp, MRP2, MRP3, and MRP4 in human and rat cryopreserved hepatocytes were investigated. In commercially available human cryopreserved hepatocytes, all drug efflux transporters except human BCRP (hBCRP) exhibited similar expression levels as in fresh liver biopsies. Expression levels of hBCRP were 60% lower in cryopreserved human hepatocytes than in liver tissue, which could lead to, at most, a 2.5-fold reduction in hBCRP-mediated efflux. Fresh rat hepatocytes showed significantly lower levels of rat BCRP compared with liver expression levels; expression levels of other ABC transporters were unchanged. ABC transporters in human cryopreserved cells were localized to the plasma membrane. Functional studies could demonstrate P-gp and BCRP activity in both human cryopreserved and fresh rat hepatocytes. Inhibiting P-gp–mediated efflux by elacridar in in vitro experiments significantly decreased fexofenadine efflux from hepatocytes, resulting in an increase in apparent fexofenadine uptake. The results from the present study clearly indicate that ABC transporter-mediated efflux in freshly isolated as well as cryopreserved rat and human hepatocytes should be taken into account in in vitro experiments used for modeling of drug metabolism and disposition.

Footnotes

    • Received August 26, 2013.
    • Accepted January 6, 2014.
  • dx.doi.org/10.1124/dmd.113.054528.

  • ↵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

ABC Efflux Transporters in Cryopreserved Hepatocytes

Patrik Lundquist, Gunilla Englund, Cristine Skogastierna, Johan Lööf, Jenny Johansson, Janet Hoogstraate, Lovisa Afzelius and Tommy B. Andersson
Drug Metabolism and Disposition March 1, 2014, 42 (3) 448-458; DOI: https://doi.org/10.1124/dmd.113.054528

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Research ArticleArticle

ABC Efflux Transporters in Cryopreserved Hepatocytes

Patrik Lundquist, Gunilla Englund, Cristine Skogastierna, Johan Lööf, Jenny Johansson, Janet Hoogstraate, Lovisa Afzelius and Tommy B. Andersson
Drug Metabolism and Disposition March 1, 2014, 42 (3) 448-458; DOI: https://doi.org/10.1124/dmd.113.054528
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