In vivo imaging of hepatobiliary transport function mediated by multidrug resistance associated protein and P-glycoprotein.
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 microM), 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.
Hendrikse
N Harry
NH
PET Center, University Hospital Groningen, The Netherlands. n.h.hendrikse@pet.azg.nl
Kuipers
Folkert
F
Meijer
Coby
C
Havinga
Rick
R
Bijleveld
Charles M A
CM
van der Graaf
Winette T A
WT
Vaalburg
Willem
W
de Vries
Elisabeth G E
EG
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000494:pharmacology*; D000818:Animals; D001646:Bile / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000000981:diagnostic imaging* / Q000502:physiology; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000494:pharmacology*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013667:Technetium / Q000493:pharmacokinetics*; D019780:Technetium Tc 99m Lidofenin / Q000493:pharmacokinetics*; D017256:Technetium Tc 99m Sestamibi / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019275:Radiopharmaceuticals; D013667:Technetium; D019780:Technetium Tc 99m Lidofenin; D017256:Technetium Tc 99m Sestamibi