Transport mechanisms of hepatic uptake and bile excretion in clinical hepatobiliary scintigraphy with 99mTc-N-pyridoxyl-5-methyltryptophan

Kobayashi, Masato; Nakanishi, Takeo; Nishi, Kodai; Higaki, Yusuke; Okudaira, Hiroyuki; Ono, Masahiro; Tsujiuchi, Takafumi; Mizutani, Asuka; Nishii, Ryuichi; Tamai, Ikumi; Arano, Yasushi; Kawai, Keiichi

doi:10.1016/j.nucmedbio.2014.01.004

Cited by 18 publications

(15 citation statements)

References 20 publications

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“…For the SLC transporter experiments, Mock Flp-in-293 cells (Flp/mock), OAT1-expressing Flp-in-293 cells (Flp/OAT1) [38], mock HEK293 cells (HEK/mock), and OATP1B3-expressing HEK293 cells (HEK/OATP1B3) [39] were obtained from Kanazawa University (Ishikawa, Japan). Briefly, Flp-in-293 and HEK293 cells were transfected with the appropriate plasmid DNA and selected using antibiotics (hygromycin or G-418).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Assessment of Amino Acid/Drug Transporters for Renal Transport of [18F]Fluciclovine (anti-[18F]FACBC) in Vitro

Ono

Baden

Okudaira

et al. 2016

IJMS

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[18F]Fluciclovine (trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid; anti-[18F]FACBC), a positron emission tomography tracer used for the diagnosis of recurrent prostate cancer, is transported via amino acid transporters (AATs) with high affinity (Km: 97–230 μM). However, the mechanism underlying urinary excretion is unknown. In this study, we investigated the involvement of AATs and drug transporters in renal [18F]fluciclovine reuptake. [14C]Fluciclovine (trans-1-amino-3-fluoro[1-14C]cyclobutanecarboxylic acid) was used because of its long half-life. The involvement of AATs in [14C]fluciclovine transport was measured by apical-to-basal transport using an LLC-PK1 monolayer as model for renal proximal tubules. The contribution of drug transporters herein was assessed using vesicles/cells expressing the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated protein 4 (MRP4), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) , organic cation transporter 2 (OCT2), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporting polypeptide 1B3 (OATP1B3). The apical-to-basal transport of [14C]fluciclovine was attenuated by l-threonine, the substrate for system alanine-serine-cysteine (ASC) AATs. [14C]Fluciclovine uptake by drug transporter-expressing vesicles/cells was not significantly different from that of control vesicles/cells. Fluciclovine inhibited P-gp, MRP4, OAT1, OCT2, and OATP1B1 (IC50 > 2.95 mM). Therefore, system ASC AATs may be partly involved in the renal reuptake of [18F]fluciclovine. Further, given that [18F]fluciclovine is recognized as an inhibitor with millimolar affinity for the tested drug transporters, slow urinary excretion of [18F]fluciclovine may be mediated by system ASC AATs, but not by drug transporters.

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Section: Methodsmentioning

confidence: 99%

“…The experiments were performed as described previously [39], with minor modifications. Cells provided by Kanazawa University were seeded at a density of 5 × 10 4 cells per well in poly- d -lysine-coated 24-well flat-bottom tissue culture plates (Becton Dickinson).…”

Section: Methodsmentioning

confidence: 99%

Assessment of Amino Acid/Drug Transporters for Renal Transport of [18F]Fluciclovine (anti-[18F]FACBC) in Vitro

Ono

Baden

Okudaira

et al. 2016

IJMS

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“…Another SPECT tracer which has been used to diagnose hepatobiliary diseases is [ 99m Tc]N-pyridoxil-5-methyltryptophan ([ 99m Tc]PMT) [113][114][115]. One in vitro study showed that [ 99m Tc] PMT was mainly transported by OATP1B1 and OATP1B3 [116]; however, the in vivo transport mechanisms for uptake and efflux of [ 99m Tc]PMT in hepatocytes have not yet been elucidated. [ 111 In]Indium-ethoxybenzyl-diethylenetriaminepentaacetic acid ([ 111 In]EOB-DTPA) was derived from the MRI contrast agent Gd-EOB-DTPA (gadoxetate) and was evaluated in mice confirming higher uptake in NTCP overexpressing tumor xenografts [117].…”

Section: Spect Tracers To Study Liver Transportersmentioning

confidence: 99%

Use of imaging to assess the activity of hepatic transporters

Hernández-Lozano

Langer

2020

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Membrane transporters of the SLC and ABC families are abundantly expressed in the liver, where they control the transfer of drugs/drug metabolites across the sinusoidal and canalicular hepatocyte membranes and play a pivotal role in hepatic drug clearance. Noninvasive imaging methods, such as PET, SPECT or MRI, allow for measuring the activity of hepatic transporters in vivo, provided that suitable transporter imaging probes are available. Areas covered: We give an overview of the working principles of imaging-based assessment of hepatic transporter activity. We discuss different currently available PET/SPECT radiotracers and MRI contrast agents and their applications to measure hepatic transporter activity in health and disease. We cover mathematical modeling approaches to obtain quantitative parameters of transporter activity and provide a critical assessment of methodological limitations and challenges associated with this approach. Expert opinion: PET in combination with pharmacokinetic modeling can be potentially applied in drug development to study the distribution of new drug candidates to the liver and their clearance mechanisms. This approach bears potential to mechanistically assess transporter-mediated drug-drug interactions, to assess the influence of disease on hepatic drug disposition and to validate and refine currently available in vitro-in vivo extrapolation methods to predict hepatic clearance of drugs. ARTICLE HISTORY

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“…Like OAT1 and OAT3, OAT2 can accommodate a variety of organic anions and indeed has also been shown to transport a number of pharmacologically active agents. OAT2 has been increasingly recognized in terms of its role in drug disposition (Table 2) (Sun et al, 2001;Kobayashi et al, 2005a), H-2 receptor antagonists (cimetidine and ranitidine) (Tahara et al, 2005), diuretics (bumetanide) (Kobayashi et al, 2005a), nonsteroidal anti-inflammatory drugs (e.g., diclofenac) (Zhang et al, 2016), topoisomerase inhibitor (irinotecan) (Marada et al, 2015), and endogenous prostaglandins and hormones (e.g., prostaglandin E 2 , prostaglandin F 2 , DHEA sulfate, and E3S) (Enomoto et al, 2002b;Kobayashi et al, 2005aKobayashi et al, , 2014Jia et al, 2015) (Table 2). OAT2 has also been identified as a candidate diclofenac b-Dglucuronide transporter (Zhang et al, 2016).…”

Section: Relatively Well Understood Aspects Of Oat2mentioning

confidence: 99%

“…A compound that can selectively inhibit the basolateral influx mediated by OAT2 without blocking the uptake processes mediated by OCT1 and OATPs may be important with respect to validating the function of OAT2 in primary hepatocytes. OAT2 expressed in Xenopus oocytes and HEK293 cells is known to mediate transport of E3S (Kobayashi et al, 2005a(Kobayashi et al, , 2014, but E3S, an organic anion, is also a substrate for OATP1B1 and OATP2B1. Several early studies showed that PAH is a human OAT2 substrate, but Cropp et al (2008) observed only appreciable uptake of PAH by HEK293 cells stably transfected with OAT2 compared with the control cells.…”

Section: Underinvestigated Liver Solute Carriermentioning

confidence: 99%

Organic Anion Transporter 2: An Enigmatic Human Solute Carrier

Shen¹,

Lai²,

Rodrigues³

2016

Drug Metab Dispos

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As a member of the solute carrier 22A (SLC22A) family, organic anion transporter 2 (OAT2; SLC22A7) is emerging as an important drug transporter because of its expression in both the liver and kidney, two major eliminating organs, and its ability to transport not only a wide variety of xenobiotics but also numerous physiologically important endogenous compounds, like creatinine and cGMP. However, OAT2 has received relatively little attention compared with other OATs and solute carriers (SLCs), like organic cation transporters, sodium-dependent taurocholate cotransporting polypeptide, multidrug and toxin extrusion proteins, and organic anion-transporting polypeptides. Overall, the literature describing OAT2 is rapidly evolving, with numerous publications contradicting each other regarding the transport mechanism, tissue distribution, and transport of creatinine and cGMP, two important endogenous OAT2 substrates. Despite its status as a liver and kidney SLC, tools for assessing its activity and inhibition are lacking, and its role in drug disposition and elimination remains to be defined. The current review focuses on the available and emerging literature describing OAT2. We envision that OAT2 will gain more prominence as its expression, substrate, and inhibitor profile is investigated further and compared with other SLCs.

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Transport mechanisms of hepatic uptake and bile excretion in clinical hepatobiliary scintigraphy with 99mTc-N-pyridoxyl-5-methyltryptophan

Cited by 18 publications

References 20 publications

Assessment of Amino Acid/Drug Transporters for Renal Transport of [18F]Fluciclovine (anti-[18F]FACBC) in Vitro

Assessment of Amino Acid/Drug Transporters for Renal Transport of [18F]Fluciclovine (anti-[18F]FACBC) in Vitro

Use of imaging to assess the activity of hepatic transporters

Organic Anion Transporter 2: An Enigmatic Human Solute Carrier

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