Review
Imaging Probes and Modalities for the Study of Solute Carrier O (SLCO)-Transport Function In Vivo

https://doi.org/10.1016/j.xphs.2017.04.031Get rights and content

Abstract

Transporters of the solute carrier O (SLCO) family, former organic anion-transporting polypeptides, are now recognized as key players in pharmacokinetics. Imaging is increasingly regarded as a relevant method to elucidate and decipher the intrinsic role of SLCO in controlling drug disposition in plasma and tissues. Current research in this representative field of translational research is based on different imaging modalities including nuclear imaging, such as single-photon emission computed tomography or positron emission tomography, and magnetic resonance imaging. Imaging modalities can be compared in terms of sensitivity, quantitative properties, spatial resolution, variety of ligands, and radiation exposure. All these approaches rely on the use of SLCO substrates that are detected using corresponding modalities. The present review aims at reporting and comparing the imaging probes that have been proposed to study SLCO-transport function, in terms of in vitro specificity, in vivo behavior, and clinical validation.

Introduction

Membrane transporters are now recognized as key players in pharmacokinetics (PK). Each transporter has a specific pattern of substrates and tissue expression. Transporters of the ATP-binding cassette (ABC) and solute carrier (SLC) superfamilies expressed in the intestine, liver, and kidneys have been shown to control the absorption, distribution, and elimination of many drugs and measurably affect PK. Transporter function is also assumed to account for intra- and interindividual variability in drug PK.1 Many clinically relevant drug–drug interactions involving transporter inhibitors, inducers, and substrates have been described.2 In 2007, the International Transporter Consortium, which includes members from academia, industry, and the U.S. Food and Drug Administration, was formed with the goal of determining transporters that are of emerging importance, establishing recommendations, regulatory draft guidance documents on transporter–drug interactions, and highlighting transporter-related challenges in drug development.1, 3 In this framework, imaging is increasingly regarded as a safe and relevant method to elucidate and decipher the intrinsic role of membrane transporters in controlling drug disposition.4

Transporters expressed in blood–tissue barriers have been shown to control the tissue exposure to many compounds.2 These transporters may control the drug tissue distribution with limited impact on the plasma PK. In this framework, several imaging methods have been proposed to noninvasively unveil and quantify the impact of transporter function on drug exposure to nonclearance organs, such as the blood–brain barrier,5, 6, 7 the blood–retina barriers,8 or the blood–tumor barrier9 in animals and humans.

Section snippets

The Solute Carrier O Transporter Family

Among SLC transporters, the solute carrier O (SLCO) transporter family has been detected at many blood–tissue interfaces.10 SLCO were initially identified at the basolateral membrane of hepatocytes where they mediate the transport of bile salt and cholephilic anionic compounds10 (Fig. 1).

Today, 11 members of the SLCO family have been identified in human.11 This superfamily was originally named organic anion-transporting polypeptides (OATP) or SLC21A. The nomenclature of its members was then

Imaging SLCO Transporter Function

Noninvasive approaches are, therefore, required to elucidate or predict the impact of SLCO-mediated transport in clearance organs on drug disposition in plasma. Moreover, imaging methods would be useful to unveil and quantify the role of nonhepatic SLCO transporter function on drug distribution in organs, as a prerequisite to the local pharmacologic/toxicologic effect. In the absence of measurable concentration in tissues, conventional PK approaches do not allow for investigating the role of

Imaging Probes for SPECT

SPECT uses gamma rays detected by gamma cameras that have been readily available in most nuclear medicine departments for decades. The radionuclide gamma emitter most frequently used is metastable technetium-99 (99mTc) because of its medium energy (140 keV), relatively short half-life (T1/2 = 6.0 h), and availability through the molybdene–technetium generator. 99mTc is a radionuclide that requires forming an organic coordination complex, limiting the possibility to radiolabel substrates without

Imaging Probes for MRI

MRI is a nonirradiant imaging technique performed in radiology, using pulses of radio waves that excite the nuclear spin energy transition, and magnetic field gradients localize the signal in space. The result is pictures of anatomy and physiological process with high spatial resolution and excellent soft tissue contrast but with limited sensitivity and quantification challenges (Fig. 2). Compared with nuclear imaging, which can be performed using tracer dose of radioligands, the contrast

Imaging Probes for PET

PET is another nuclear imaging modality using β+-emitting isotopes. Thanks to a high sensitivity of PET scanners, radiopharmaceutical agents used for PET imaging can be administered at tracer dose. The advantages of PET over SPECT include higher sensitivity (detection efficiency), better temporal and spatial resolutions, at least in humans and large animals. PET imaging benefits from straightforward 3D quantifiable recordings (Fig. 2). The β+ emitter most routinely used in clinic is fluorine-18

Conclusion and Perspectives

Molecular imaging aims at developing new compounds dedicated to the study of a specific molecular target. Interestingly, current probes for SLCO imaging have often been used for decades to study hepatobiliary function in patients (99mTc-mebrofenin SPECT imaging, Gd-EOB-DTPA MRI). The importance of SLCO-mediated transport on their hepatic uptake was discovered many years after, thus providing a molecular determinant for their predominant liver accumulation.73 The main advantage of the use of

Acknowledgments

This work was funded by a grant from ANR-16-CE17-0011-001.

References (74)

  • R. Ho et al.

    Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics

    Gastroenterology

    (2006)
  • Y. Yagi et al.

    The synthesis of [18F]pitavastatin as a tracer for hOATP using the Suzuki coupling

    Org Biomol Chem

    (2015)
  • A. Koenen et al.

    Steroid hormones specifically modify the activity of organic anion transporting polypeptides

    Eur J Pharm Sci

    (2012)
  • C. Gedeon et al.

    Transport of glyburide by placental ABC transporters: implications in fetal drug exposure

    Placenta

    (2006)
  • E. Pollex et al.

    The role of placental breast cancer resistance protein in the efflux of glyburide across the human placenta

    Placenta

    (2008)
  • S.J. Hemauer et al.

    Role of human placental apical membrane transporters in the efflux of glyburide, rosiglitazone, and metformin

    Am J Obstet Gynecol

    (2010)
  • K.M. Giacomini et al.

    Membrane transporters in drug development

    Nat Rev Drug Discov

    (2010)
  • J. König et al.

    Transporters and drug-drug interactions: important determinants of drug disposition and effects

    Pharmacol Rev

    (2013)
  • M.J. Zamek-Gliszczynski et al.

    Highlights from the International transporter Consortium second workshop

    Clin Pharmacol Ther

    (2012)
  • H. Kusuhara

    Imaging in the study of membrane transporters

    Clin Pharmacol Ther

    (2013)
  • M. Muzi et al.

    Imaging of cyclosporine inhibition of P-glycoprotein activity using 11C-verapamil in the brain: studies of healthy humans

    J Nucl Med

    (2009)
  • W.C. Kreisl et al.

    P-glycoprotein function at the blood-brain barrier in humans can be quantified with the substrate radiotracer 11C-N-desmethyl-loperamide

    J Nucl Med

    (2010)
  • G. Pottier et al.

    Imaging the impact of the P-glycoprotein (Abcb1) function on the brain kinetics of metoclopramide

    J Nucl Med

    (2016)
  • M. Bauer et al.

    Assessment of P-glycoprotein transport activity at the human blood-retinal barrier with (R)-11C-verapamil PET

    J Nucl Med

    (2017)
  • P. Kannan et al.

    Imaging the function of P-glycoprotein with radiotracers: pharmacokinetics and in vivo applications

    Clin Pharmacol Ther

    (2009)
  • M. Roth et al.

    OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SCL22A gene superfamilies

    Br J Pharmacol

    (2012)
  • A. Obaidat et al.

    The expression and function of organic anion transporting polypeptides in normal tissues and in cancer

    Annu Rev Pharmacol Toxicol

    (2012)
  • B. Hagenbuch et al.

    Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family

    Xenobiotica

    (2008)
  • A. Kalliokoski et al.

    Impact of OATP transporters on pharmacokinetics

    Br J Pharmacol

    (2009)
  • Y. Shitara et al.

    Clinical significance of organic anion transporting polypeptides (OATPs) in drug disposition: their roles in hepatic clearance and intestinal absorption

    Biopharm Drug Dispos

    (2013)
  • X. Chu et al.

    Species differences in drug transporters and implications for translating preclinical findings to humans

    Expert Opin Drug Metab Toxicol

    (2013)
  • A. Mann et al.

    Molecular imaging of membrane transporters’ activity in cancer: a picture is worth a thousand tubes

    AAPS J

    (2015)
  • T. Takashima et al.

    Positron emission tomography studies using (15R)-16-m-[11C]tolyl-17,18,19,20-tetranorisocarbacyclin methyl ester for the evaluation of hepatobiliary transport

    J Pharmacol Exp Ther

    (2010)
  • T. Takashima et al.

    PET imaging–based evaluation of hepatobiliary transport in humans with (15R)-11C-TIC-Me

    J Nucl Med

    (2012)
  • D.L. Bailey et al.

    An evidence-based review of quantitative SPECT imaging and potential clinical applications

    J Nucl Med

    (2013)
  • G. Ghibellini et al.

    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)
  • S. Neyt et al.

    In vivo visualization and quantification of (disturbed) Oatp-mediated hepatic uptake and Mrp2-mediated biliary excretion of 99mTc-mebrofenin in mice

    J Nucl Med

    (2013)
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