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

Autor: Hendrikse, N. Harry, Kuipers, Folkert, Meijer, Coby, Havinga, Rick, Bijleveld, Charles M. A., van der Graaf, Winette T. A., Vaalburg, Willem, de Vries, Elisabeth G. E.
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Zdroj: Cancer Chemotherapy & Pharmacology; Aug2004, Vol. 54 Issue 2, p131-138, 8p
Abstrakt: 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 agents99mTc-HIDA and99mTc-MIBI, which are used clinically for myocardial perfusion measurements; and (2) to deduce MRP and P-gp functions in vivo from hepatic99mTc 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 cellular99mTc-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 of99mTc-HIDA was impaired in GY/TR- compared to control rats and not affected by glutathione depletion in GY/TR- rats. Hepatic secretion of99mTc-HIDA was slower in GY/TR- (t1/2 40 min) than in control rats (t1/2 7 min). Bile secretion of99mTc-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, while99mTc-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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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