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In vivo visualization and quantification of (disturbed) Oatp-mediated hepatic uptake and Mrp2-mediated biliary excretion of 99mTc-mebrofenin in mice

Sara Neyt UGent, Maarten T Huisman, Christian Vanhove UGent, Hilde De Man, Maarten Vliegen, LIESELOTTE MOERMAN UGent, Caroline Dumolyn UGent, Geert Mannens and Filip De Vos UGent (2013) JOURNAL OF NUCLEAR MEDICINE. 54(4). p.624-630
abstract
Hepatic transport of Tc-99m-mebrofenin through organic anion transport protein 1a and 1b (Oatp1a/1b) and multidrug resistance protein 2 (Mrp2) was investigated by small-animal SPECT. On the basis of the results, a noninvasive method to visualize and quantify disturbances in hepatic transport is proposed. Methods: Friend virus B wild-type mice (untreated, bile duct-ligated, vehicle-or rifampicin-treated) and strain-matched knockout mice unable to express the uptake transporters Oatp1a/1b (Slco1a/1b(-/-)/(-/-)) or the efflux transporter Mrp2 (Abcc2(-/-)) were intravenously injected with Tc-99m-mebrofenin (n = 3 per group). After dynamic small-animal SPECT and short CT acquisitions, time-activity curves of the liver and of the gallbladder and intestines were obtained and correlated with direct blood samples. Results: Normal hepatobiliary clearance of Tc-99m-mebrofenin was severely impaired in the bile duct-ligated animal, as evidenced by elevated hepatic tracer levels. In Slco1a/1b2(-/-)/(-/-) mice, a lower area under the curve (AUC) for the liver (P = 0.014) was obtained and no activity was detected in the gallbladder and intestines. Renal rerouting was observed, along with an increase in the blood AUC (P = 0.01). Abcc2(-/-) mice had a higher liver AUC (P = 0.009), a delayed emergence time of Tc-99m-mebrofenin in the gallbladder (P = 0.009), and a lower AUC for the gallbladder and intestines (P = 0.001). The blood curve was similar to that of wild-type mice. Tc-99m-mebrofenin disposition was altered after rifampicin treatments. We observed a dose-dependent delayed time point at which tracer maximized in liver, an increased AUC for liver, and a lower AUC for gallbladder and intestines (P = 0.042, 0.034, and 0.001, respectively, highest dose). Emergence in the gallbladder occurred later (P = 0.009, highest dose), and blood AUC was higher (P = 0.006). Conclusion: The current study visualized and quantified hepatic uptake and biliary efflux of Tc-99m-mebrofenin. Our results demonstrated the possibility of discriminating, on a quantitative level, between lack of functional activity of sinusoidal uptake versus that of biliary efflux transporters.
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author
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alternative title
In vivo visualization and quantification of (disturbed) Oatp-mediated hepatic uptake and Mrp2-mediated biliary excretion of Tc-99m-mebrofenin in mice
year
type
journalArticle (original)
publication status
published
subject
keyword
HEPATOBILIARY TRANSPORT, BILE-ACID TRANSPORTERS, DRUGS, RIFAMPICIN, MRP2, Tc-99m-mebrofenin, hepatobiliary transport, small-animal SPECT, Mrp2, Oatp1a/1b
journal title
JOURNAL OF NUCLEAR MEDICINE
J. Nucl. Med.
volume
54
issue
4
pages
624 - 630
Web of Science type
Article
Web of Science id
000316939200024
JCR category
RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING
JCR impact factor
5.563 (2013)
JCR rank
6/122 (2013)
JCR quartile
1 (2013)
ISSN
0161-5505
DOI
10.2967/jnumed.112.108233
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2119049
handle
http://hdl.handle.net/1854/LU-2119049
date created
2012-05-30 09:06:01
date last changed
2014-09-19 12:52:25
@article{2119049,
  abstract     = {Hepatic transport of Tc-99m-mebrofenin through organic anion transport protein 1a and 1b (Oatp1a/1b) and multidrug resistance protein 2 (Mrp2) was investigated by small-animal SPECT. On the basis of the results, a noninvasive method to visualize and quantify disturbances in hepatic transport is proposed. Methods: Friend virus B wild-type mice (untreated, bile duct-ligated, vehicle-or rifampicin-treated) and strain-matched knockout mice unable to express the uptake transporters Oatp1a/1b (Slco1a/1b(-/-)/(-/-)) or the efflux transporter Mrp2 (Abcc2(-/-)) were intravenously injected with Tc-99m-mebrofenin (n = 3 per group). After dynamic small-animal SPECT and short CT acquisitions, time-activity curves of the liver and of the gallbladder and intestines were obtained and correlated with direct blood samples. Results: Normal hepatobiliary clearance of Tc-99m-mebrofenin was severely impaired in the bile duct-ligated animal, as evidenced by elevated hepatic tracer levels. In Slco1a/1b2(-/-)/(-/-) mice, a lower area under the curve (AUC) for the liver (P = 0.014) was obtained and no activity was detected in the gallbladder and intestines. Renal rerouting was observed, along with an increase in the blood AUC (P = 0.01). Abcc2(-/-) mice had a higher liver AUC (P = 0.009), a delayed emergence time of Tc-99m-mebrofenin in the gallbladder (P = 0.009), and a lower AUC for the gallbladder and intestines (P = 0.001). The blood curve was similar to that of wild-type mice. Tc-99m-mebrofenin disposition was altered after rifampicin treatments. We observed a dose-dependent delayed time point at which tracer maximized in liver, an increased AUC for liver, and a lower AUC for gallbladder and intestines (P = 0.042, 0.034, and 0.001, respectively, highest dose). Emergence in the gallbladder occurred later (P = 0.009, highest dose), and blood AUC was higher (P = 0.006). Conclusion: The current study visualized and quantified hepatic uptake and biliary efflux of Tc-99m-mebrofenin. Our results demonstrated the possibility of discriminating, on a quantitative level, between lack of functional activity of sinusoidal uptake versus that of biliary efflux transporters.},
  author       = {Neyt, Sara and Huisman, Maarten T and Vanhove, Christian and De Man, Hilde and Vliegen, Maarten and MOERMAN, LIESELOTTE and Dumolyn, Caroline and Mannens, Geert and De Vos, Filip},
  issn         = {0161-5505},
  journal      = {JOURNAL OF NUCLEAR MEDICINE},
  keyword      = {HEPATOBILIARY TRANSPORT,BILE-ACID TRANSPORTERS,DRUGS,RIFAMPICIN,MRP2,Tc-99m-mebrofenin,hepatobiliary transport,small-animal SPECT,Mrp2,Oatp1a/1b},
  language     = {eng},
  number       = {4},
  pages        = {624--630},
  title        = {In vivo visualization and quantification of (disturbed) Oatp-mediated hepatic uptake and Mrp2-mediated biliary excretion of 99mTc-mebrofenin in mice},
  url          = {http://dx.doi.org/10.2967/jnumed.112.108233},
  volume       = {54},
  year         = {2013},
}

Chicago
Neyt, Sara, Maarten T Huisman, Christian Vanhove, Hilde De Man, Maarten Vliegen, LIESELOTTE MOERMAN, Caroline Dumolyn, Geert Mannens, and Filip De Vos. 2013. “In Vivo Visualization and Quantification of (disturbed) Oatp-mediated Hepatic Uptake and Mrp2-mediated Biliary Excretion of 99mTc-mebrofenin in Mice.” Journal of Nuclear Medicine 54 (4): 624–630.
APA
Neyt, S., Huisman, M. T., Vanhove, C., De Man, H., Vliegen, M., MOERMAN, L., Dumolyn, C., et al. (2013). In vivo visualization and quantification of (disturbed) Oatp-mediated hepatic uptake and Mrp2-mediated biliary excretion of 99mTc-mebrofenin in mice. JOURNAL OF NUCLEAR MEDICINE, 54(4), 624–630.
Vancouver
1.
Neyt S, Huisman MT, Vanhove C, De Man H, Vliegen M, MOERMAN L, et al. In vivo visualization and quantification of (disturbed) Oatp-mediated hepatic uptake and Mrp2-mediated biliary excretion of 99mTc-mebrofenin in mice. JOURNAL OF NUCLEAR MEDICINE. 2013;54(4):624–30.
MLA
Neyt, Sara, Maarten T Huisman, Christian Vanhove, et al. “In Vivo Visualization and Quantification of (disturbed) Oatp-mediated Hepatic Uptake and Mrp2-mediated Biliary Excretion of 99mTc-mebrofenin in Mice.” JOURNAL OF NUCLEAR MEDICINE 54.4 (2013): 624–630. Print.