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 microM) to 10% and 4% of control, respectively. MEB (0.4 nM) 
transport by MRP2 was inhibited to 12% of control by MK571 (50 microM); 
MRP3-mediated transport was inhibited to 5% of control by 
estradiol-17-beta-glucuronide (100 microM). 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.