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In vivo imaging of hepatobiliary transport function mediated by multidrug resistance associated protein and P-glycoprotein

Cancer Chemotherapy and Pharmacology volume 54, pages 131–138 (2004)Cite this article

Abstract

Multidrug resistance associated proteins (MRPs) and P-glycoprotein (P-gp) are involved in hepatobiliary transport of various compounds. Our aim was (1) to define transporter specificity of the cholescintigraphic agents 99mTc-HIDA and 99mTc-MIBI, which are used clinically for myocardial perfusion measurements; and (2) to deduce MRP and P-gp functions in vivo from hepatic 99mTc kinetics. Accumulation of radioactivity was measured in the human tumor cell lines GLC4, GLC4/ADR150x (MRP1-overexpressing/P-gp-negative) and GLC4/P-gp (P-gp-overexpressing). Bile secretion was quantified in untreated and in glutathione-depleted control and MRP2-deficient (GY/TR−) rats. Hepatobiliary transport was measured using a gamma camera in both types of rats. 99mTc-HIDA accumulated 5.8-fold less in GLC4/ADR150x calls than in GLC4 or GLC4/P-gp cells. In GLC4/ADR150x, the cellular 99mTc-HIDA content was increased 3.4-fold by the MRP1,2 inhibitor MK571 (50 μM), while MK571 had no measurable effect in GLC4 and GLC4/P-gp cells. 99mTc-MIBI accumulated less in GLC4/P-gp and GLC4/ADR150x cells than in GLC4 cells. Bile secretion of 99mTc-HIDA was impaired in GY/TR− compared to control rats and not affected by glutathione depletion in GY/TR− rats. Hepatic secretion of 99mTc-HIDA was slower in GY/TR− (t1/2 40 min) than in control rats (t1/2 7 min). Bile secretion of 99mTc-MIBI was similar in both rat strains and impaired by glutathione depletion in control rats only, indicating compensatory activity of additional transporter(s) in GY/TR− rats. 99mTc-HIDA is transported only by MRP1,2 only, while 99mTc-MIBI is transported by P-gp and MRP1,2. The results indicate that hepatic P-gp and MRP1,2 function can be assessed in vivo by sequential use of both radiopharmaceuticals.

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Fig. 1
Fig. 2a, b
Fig. 3a–d
Fig. 4a, b
Fig. 5a, b

Abbreviations

DEM:

Diethylmaleate

GLC4 :

Small-cell lung carcinoma

GSH:

Glutathione

P-gp:

P-Glycoprotein

MRP:

Multidrug resistance associated protein

99mTc-HIDA:

99mTechnetium-disofenin

99mTc-MIBI:

99mTechnetium-sestamibi

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Acknowledgement

This study was supported by grant GUKC 94-783 from the Dutch Cancer Society.

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Affiliations

  1. PET Center, University Hospital Groningen, Groningen, The Netherlands

    N. Harry Hendrikse & Willem Vaalburg

  2. Department of Pediatrics, University Hospital Groningen, Groningen, The Netherlands

    Folkert Kuipers, Rick Havinga & Charles M. A. Bijleveld

  3. Department of Medical Oncology, University Hospital Groningen, Groningen, The Netherlands

    Coby Meijer, Winette T. A. van der Graaf & Elisabeth G. E. de Vries

Authors
  1. N. Harry Hendrikse
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  2. Folkert Kuipers
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  3. Coby Meijer
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  4. Rick Havinga
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  5. Charles M. A. Bijleveld
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  6. Winette T. A. van der Graaf
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  7. Willem Vaalburg
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  8. Elisabeth G. E. de Vries
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Correspondence to N. Harry Hendrikse.

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Hendrikse, N.H., Kuipers, F., Meijer, C. et al. In vivo imaging of hepatobiliary transport function mediated by multidrug resistance associated protein and P-glycoprotein. Cancer Chemother Pharmacol 54, 131–138 (2004). https://doi.org/10.1007/s00280-004-0793-2

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  • DOI: https://doi.org/10.1007/s00280-004-0793-2

Keywords

  • GY/TR−
  • 99mTechnetium
  • Liver
  • P-gp
  • MRP
  • Functional imaging