Abstract
Purpose
Transport of the hepatobiliary scintigraphy agent Tc-99m mebrofenin (MEB) was characterized and simulation studies were conducted to examine the effects of altered hepatic transport on MEB pharmacokinetics in humans.
Methods
MEB transport was investigated in Xenopus laevis oocytes expressing OATP1B1 or OATP1B3, and in membrane vesicles prepared from HEK293 cells transfected with MRP2 or MRP3. A pharmacokinetic model was developed based on blood, urine and bile concentration-time profiles obtained in healthy humans, and the effect of changes in hepatic uptake and/or excretion associated with disease states (hyperbilirubinemia and cholestasis) on MEB disposition was simulated.
Results
MEB (80 pM) transport by OATP1B1 and OATP1B3 was inhibited by rifampicin (50 μM) to 10% and 4% of control, respectively. MEB (0.4 nM) transport by MRP2 was inhibited to 12% of control by MK571 (50 μM); MRP3-mediated transport was inhibited to 5% of control by estradiol-17-beta-glucuronide (100 μM). A two-compartment model described MEB (2.5 mCi) systemic disposition in humans (systemic clearance = 16.2 ± 2.7 ml min−1 kg−1); biliary excretion was the predominant route of hepatic elimination (efflux rate constants ratio canalicular/sinusoidal = 3.4 ± 0.8). Based on simulations, altered hepatic transport markedly influenced MEB systemic and hepatic exposure.
Conclusions
MEB may be a useful probe to assess how altered hepatic function at the transport level modulates hepatobiliary drug disposition.
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Abbreviations
- EF:
-
gallbladder ejection fraction
- E217βG:
-
estradiol 17-β-d-glucuronide
- GB:
-
gamma counts over gallbladder region
- HEK293:
-
human embryonic kidney cells
- HIDA:
-
hepatobiliary imino diacetic acid
- MEB:
-
Tc-99m mebrofenin
- MRP:
-
multidrug resistance-associated protein
- OATP:
-
organic anion transporting polypeptide
- OR-2:
-
oocyte Ringer’s 2 buffer
- Tc-99m:
-
99mtechnetium
- TR− :
-
Mrp2 transport-deficient Wistar rat
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Acknowledgements
This work was supported by National Institutes of Health grant R01 GM41935 and grant RR00046 from the GCRC program of the Division of Research Resources. Giulia Ghibellini was the recipient of an American Foundation for Pharmaceutical Education Predoctoral Fellowship, Elaine M. Leslie was the recipient of a Postdoctoral Fellowship from the Canadian Institutes of Health Research (CIHR).
Drs. Richard Kowalsky, Daniel Bow, Joe Polli and Brendan Johnson are gratefully acknowledged for their expertise and help in the execution of the in vitro and in vivo studies. Drs. Susan P.C. Cole and Roger G. Deeley (Queen’s University) kindly provided the MRP2 and MRP3 vectors.
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Ghibellini, G., Leslie, E.M., Pollack, G.M. et al. Use of Tc-99m Mebrofenin as a Clinical Probe to Assess Altered Hepatobiliary Transport: Integration of In Vitro, Pharmacokinetic Modeling, and Simulation Studies. Pharm Res 25, 1851–1860 (2008). https://doi.org/10.1007/s11095-008-9597-0
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DOI: https://doi.org/10.1007/s11095-008-9597-0