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Analysis of Hepatic Transport Proteins

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Transporters in Drug Development

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 7))

Abstract

The liver is the major organ responsible for the elimination of endogenous and exogenous compounds via metabolism and/or excretion. Hepatocytes, the predominant cell type in the liver, are polarized cells with discrete basolateral and apical membranes. In this chapter, localization and function of hepatic transport proteins responsible for hepatobiliary drug disposition in humans are introduced. Hepatic transport proteins on the basolateral membrane mediate influx of compounds from sinusoidal blood into hepatocytes (i.e., NTCP, OATPs, OATs, OCTs) or efflux from hepatocytes back to sinusoidal blood (i.e., MRP3-6, OSTα/β). Canalicular transport proteins such as BSEP, MDR3, P-gp, BCRP, MRP2, and MATE1 are responsible for biliary excretion of compounds. Furthermore, in vitro (i.e., membrane vesicles, transfected cell systems, hepatocytes, isolated perfused liver) and in vivo (i.e., biliary excretion studies, hepatobiliary imaging techniques) model systems and methods that are used to investigate hepatic transport proteins are discussed, and their applications, advantages, and disadvantages are considered.

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Abbreviations

99mTc-HIDA:

99mTc-N(2,6-dimethylphenyl carbamoylmethyl) iminodiacetic acid

ABC:

ATP-binding cassette

AMP:

Adenosine monophosphate

ATP:

Adenosine triphosphate

AUC:

Area under the concentration–time curve

BCRP:

Breast cancer resistance protein

bLPM:

Basolateral liver plasma membrane

BSEP:

Bile salt export pump

BSP:

Bromosulfophthalein

CF-1 mice:

Mdr1a-deficient mice

cLPM:

Canalicular liver plasma membrane

CYP450:

Cytochrome P450

DDI:

Drug–drug interaction

DHEAS:

Dehydroepiandrosterone sulfate

DILI:

Drug-induced liver injury

DJS:

Dubin–Johnson syndrome

E1S:

Estrone 3-sulfate

E217G:

Estradiol-17β-D-glucuronide

EHBR:

Eisai-hyperbilirubinemic Sprague–Dawley rats

FXR:

Farnesoid X receptor

Gd-BOPTA:

Gadobenate dimeglumine

Gd-EOB-DPTA:

Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid

HBSS:

Hanks-balanced salt solution

HCC:

Hepatocellular carcinoma

HEK cells:

Human embryonic kidney cells

HMG-CoA:

3-Hydroxy-3-methyl-glutaryl coenzyme A

HPLC:

High-performance liquid chromatography

IPL:

Isolated perfused liver

iPS cells:

Inducible pluripotent stem cells

K m :

Michaelis–Menten constant

LC/MS:

Liquid chromatography mass spectrometry

LLC-PK1 cells:

Porcine kidney epithelial cells

MATE:

Multidrug and toxin extrusion

MDCK cells:

Madin–Darby canine kidney cells

MDR:

Multidrug resistance

MRI:

Magnetic-resonance imaging

MRP:

Multidrug resistance-associated protein

NCE:

New chemical entity

NTCP:

Sodium taurocholate cotransporting polypeptide (human)

Ntcp:

Sodium taurocholate cotransporting polypeptide (other species than human)

OAT:

Organic anion transporter

OATP:

Organic anion transporting polypeptide

OST:

Organic solute transporter

PBC:

Primary biliary cirrhosis

PET:

Positron emission tomography

PFIC2:

Progressive familial intrahepatic cholestasis type 2

PFIC3:

Progressive familial intrahepatic cholestasis type 3

Pgp:

P-glycoprotein

RNA:

Ribonucleic acid

RNAi:

RNA interference

SCH:

Sandwich-cultured hepatocytes

SD rat:

Sprague–Dawley rat

shRNA:

Short hairpin RNA

siRNA:

Small interfering RNA

SLC:

Solute carrier

SLCO:

Solute carrier organic anion

SPECT:

Single-photon emission computed tomography

TR− rat:

Mrp2-deficient Wistar rat

UGT:

Uridine diphosphate glucuronosyl transferase

V max :

Maximal transport velocity

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Acknowledgements

The authors are grateful for the helpful advice of Drs. Hoffmaster and Swift in the preparation of this chapter. This work was supported, in part, by a grant from the National Institute of General Medical Sciences of the National Institutes of Health under award number R01 GM41935 [K.L.R.B] and the German Research Foundation under award number Ko4186/1-1 [K.K]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Kyunghee Yang, Kathleen Köck & Kim L. R. Brouwer Pharm.D., Ph.D.

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  1. Kyunghee Yang
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  2. Kathleen Köck
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  3. Kim L. R. Brouwer Pharm.D., Ph.D.
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Correspondence to Kim L. R. Brouwer Pharm.D., Ph.D. .

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  1. The University of Tokyo Graduate School of Pharmac. Sciences, Tokyo, Japan

    Yuichi Sugiyama

  2. Pharma, Drug Transporters in ADME Department of Pharmacy, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark

    Bente Steffansen

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Yang, K., Köck, K., Brouwer, K.L.R. (2013). Analysis of Hepatic Transport Proteins. In: Sugiyama, Y., Steffansen, B. (eds) Transporters in Drug Development. AAPS Advances in the Pharmaceutical Sciences Series, vol 7. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8229-1_9

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