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