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.

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.

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.

MEB may be a useful probe to assess how altered hepatic function at the transport level modulates hepatobiliary drug disposition.