Integration of preclinical and clinical data with pharmacokinetic modeling and simulation to evaluate fexofenadine as a probe for hepatobiliary transport function

Pharm Res. 2009 Aug;26(8):1942-51. doi: 10.1007/s11095-009-9909-z. Epub 2009 Jun 4.


Purpose: The suitability of fexofenadine as a probe substrate to assess hepatobiliary transport function in humans was evaluated by pharmacokinetic modeling/simulation and in vitro/in situ studies using chemical modulators.

Methods: Simulations based on a pharmacokinetic model developed to describe fexofenadine disposition in humans were conducted to examine the impact of altered hepatobiliary transport on fexofenadine disposition. The effect of GF120918 on fexofenadine disposition was evaluated in human sandwich-cultured hepatocytes (SCH). Additionally, the effect of GF120918, bosentan, and taurocholate on fexofenadine disposition in perfused livers from TR(-) Wistar rats was examined.

Results: Based on modeling/simulation, fexofenadine systemic exposure was most sensitive to changes in the hepatic uptake rate constant, and did not reflect changes in hepatic exposure due to altered hepatic efflux. GF120918 did not impair fexofenadine biliary excretion in human SCH. GF120918 coadministration significantly decreased Cl'(biliary) to 27.5% of control in perfused rat livers.

Conclusions: Simulations were in agreement with perfused liver data which predicted changes in fexofenadine systemic exposure primarily due to altered hepatic uptake. Fexofenadine is not a suitable probe to assess hepatic efflux function based on systemic concentrations. GF120918-sensitive protein(s) mediate fexofenadine biliary excretion in rat liver, whereas in human hepatocytes multiple efflux proteins are involved in fexofenadine hepatobiliary disposition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biliary Tract / metabolism*
  • Cells, Cultured
  • Histamine H1 Antagonists, Non-Sedating / pharmacokinetics*
  • Humans
  • Liver / metabolism*
  • Models, Biological*
  • Molecular Probes
  • Rats
  • Rats, Wistar
  • Terfenadine / analogs & derivatives*
  • Terfenadine / pharmacokinetics


  • Histamine H1 Antagonists, Non-Sedating
  • Molecular Probes
  • Terfenadine
  • fexofenadine