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Integration of Preclinical and Clinical Data with Pharmacokinetic Modeling and Simulation to Evaluate Fexofenadine as a Probe for Hepatobiliary Transport Function

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Abstract

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.

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Abbreviations

ABC:

ATP binding cassette

AUC:

area under the curve

BCA:

Bicinchoninic acid

Bcrp:

breast cancer resistance protein

Bsep:

bile salt export pump

DMEM:

Dulbecco’s modified Eagle’s medium

EHBR:

Eisai hyperbilirubinemic rats

FBS:

Fetal bovine serum

GF120918:

N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide

HBSS:

Hanks’ balanced salt solution

LC/MS/MS:

liquid chromatography with detection by tandem mass spectrometry

MDR1:

multidrug resistance protein 1

Mrp:

multidrug resistance-associated protein

OATP:

organic anion transporting polypeptide

P-gp:

P-glycoprotein

SCH:

sandwich-cultured hepatocytes

TR- :

Mrp2-deficient Wistar rat

WT:

wild-type Wistar rat

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ACKNOWLEDGMENT

The authors would like to thank Arlene S. Bridges, Ph. D. for her analytical support, and Yiwei Rong, for her technical expertise in the isolation of human hepatocytes. This research was supported by a grant from the National Institutes of Health (R01 GM41935). Brandon Swift is supported by an Eli Lilly predoctoral fellowship.

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  1. Xianbin Tian

    Present address: Archemix Corporation, 300 Third St., Cambridge, Massachusetts, 02142, USA

Authors and Affiliations

  1. Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, 311 Pharmacy Lane, C.B. #7360 Kerr Hall, Chapel Hill, North Carolina, 27599-7360, USA

    Brandon Swift, Xianbin Tian & Kim L. R. Brouwer

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  1. Brandon Swift
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Correspondence to Kim L. R. Brouwer.

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Swift, B., Tian, X. & Brouwer, K.L.R. Integration of Preclinical and Clinical Data with Pharmacokinetic Modeling and Simulation to Evaluate Fexofenadine as a Probe for Hepatobiliary Transport Function. Pharm Res 26, 1942–1951 (2009). https://doi.org/10.1007/s11095-009-9909-z

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  • DOI: https://doi.org/10.1007/s11095-009-9909-z

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