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. 2008 Aug;25(8):1851-60. doi: 10.1007/s11095-008-9597-0. Epub 2008 May 30.

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 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bile / metabolism*
  • Biological Transport
  • Biological Transport, Active
  • Cell Membrane / metabolism
  • Cholestasis / metabolism
  • Computer Simulation
  • Estradiol / metabolism
  • Genetic Vectors
  • Humans
  • Hyperbilirubinemia / metabolism
  • Imino Acids* / pharmacokinetics
  • Liver / metabolism*
  • Liver-Specific Organic Anion Transporter 1
  • Models, Statistical
  • Multidrug Resistance-Associated Proteins / metabolism
  • Oocytes / metabolism
  • Organic Anion Transporters / metabolism
  • Organic Anion Transporters, Sodium-Independent / metabolism
  • Organotechnetium Compounds* / pharmacokinetics
  • Protein Binding
  • Radiopharmaceuticals* / pharmacokinetics
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Xenopus laevis

Substances

  • Imino Acids
  • Liver-Specific Organic Anion Transporter 1
  • Multidrug Resistance-Associated Proteins
  • Organic Anion Transporters
  • Organic Anion Transporters, Sodium-Independent
  • Organotechnetium Compounds
  • Radiopharmaceuticals
  • SLCO1B1 protein, human
  • SLCO1B3 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • multidrug resistance-associated protein 3
  • multidrug resistance-associated protein 2
  • Estradiol
  • technetium Tc 99m mebrofenin