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Article ; Online: Conversion of Olmesartan to Olmesartan Medoxomil, A Prodrug that Improves Intestinal Absorption, Confers Substrate Recognition by OATP2B1.

Fukazawa, Naomi / Nishimura, Tomohiro / Orii, Keisuke / Noguchi, Saki / Tomi, Masatoshi

2024

Abstract: Purpose: Olmesartan medoxomil (olmesartan-MX), an ester-type prodrug of the angiotensin II receptor blocker (ARB) olmesartan, is predominantly anionic at intestinal pH. Human organic anion transporting polypeptide 2B1 (OATP2B1) is expressed in the small ...

Abstract	Purpose: Olmesartan medoxomil (olmesartan-MX), an ester-type prodrug of the angiotensin II receptor blocker (ARB) olmesartan, is predominantly anionic at intestinal pH. Human organic anion transporting polypeptide 2B1 (OATP2B1) is expressed in the small intestine and is involved in the absorption of various acidic drugs. This study was designed to test the hypothesis that OATP2B1-mediated uptake contributes to the enhanced intestinal absorption of olmesartan-MX, even though olmesartan itself is not a substrate of OATP2B1. Methods: Tetracycline-inducible human OATP2B1- and rat Oatp2b1-overexpressing HEK 293 cell lines (hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293, respectively) were established to characterize OATP2B1-mediated uptake. Rat jejunal permeability was measured using Ussing chambers. ARBs were quantified by liquid chromatography-tandem mass spectrometry. Results: Significant olmesartan-MX uptake was observed in hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293 cells, whereas olmesartan uptake was undetectable or much lower than olmesartan-MX uptake, respectively. Furthermore, olmesartan-MX exhibited several-fold higher uptake in Caco-2 cells and greater permeability in rat jejunum compared to olmesartan. Olmesartan-MX uptake in hOATP2B1/T-REx-293 cells and in Caco-2 cells was significantly decreased by OATP2B1 substrates/inhibitors such as 1 mM estrone-3-sulfate, 100 µM rifamycin SV, and 100 µM fluvastatin. Rat Oatp2b1-mediated uptake and rat jejunal permeability of olmesartan-MX were significantly decreased by 50 µM naringin, an OATP2B1 inhibitor. Oral administration of olmesartan-MX with 50 µM naringin to rats significantly reduced the area under the plasma concentration-time curve of olmesartan to 76.9%. Conclusion: Olmesartan-MX is a substrate for OATP2B1, and the naringin-sensitive transport system contributes to the improved intestinal absorption of olmesartan-MX compared with its parent drug, olmesartan.
Language	English
Publishing date	2024-03-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	843063-9
ISSN	1573-904X ; 0724-8741 ; 0739-0742
ISSN (online)	1573-904X
ISSN	0724-8741 ; 0739-0742
DOI	10.1007/s11095-024-03687-1
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Article ; Online: L-type Amino Acid Transporter 1 (SLC7A5)-Mediated Transport of Pregabalin at the Rat Blood-Spinal Cord Barrier and its Sensitivity to Plasma Branched-Chain Amino Acids.

Akashi, Tomoya / Noguchi, Saki / Takahashi, Yu / Nishimura, Tomohiro / Tomi, Masatoshi

Journal of pharmaceutical sciences

2023 Volume 112, Issue 4, Page(s) 1137–1144

Abstract: Pregabalin is an anti-neuropathic pain drug inhibiting the α2δ subunit of the voltage-dependent calcium channel in the spinal cord. The aim of this study is to characterize the transport mechanism of pregabalin at the blood-spinal cord barrier (BSCB) by ... ...

Abstract	Pregabalin is an anti-neuropathic pain drug inhibiting the α2δ subunit of the voltage-dependent calcium channel in the spinal cord. The aim of this study is to characterize the transport mechanism of pregabalin at the blood-spinal cord barrier (BSCB) by means of in vivo experiments in rats and in vitro studies using primary-cultured rat spinal cord endothelial cells. We isolated endothelial cells by culturing rat spinal cord tissue in the presence of puromycin, and confirmed the expression of BSCB markers such as Cd31, Mdr1a, and Claudin-5. The uptake of pregabalin by primary-cultured rat spinal cord endothelial cells was sodium-independent and was significantly inhibited by L-leucine, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, and JPH203. These results suggest the involvement of L-type amino acid transporter (LAT) 1. LAT1 mRNA and protein was expressed in primary-cultured rat spinal cord endothelial cells, which is consistent with LAT1 expression at the BSCB. In the in vivo study, the transfer of pregabalin to rat spinal cord and brain was significantly decreased by the pre-administration of branched chain amino acids (BCAAs), which are endogenous substrates of LAT1. Our results indicate that pregabalin transport across the BSCB is mediated at least in part by LAT1 and is inhibited by plasma BCAAs.
MeSH term(s)	Rats ; Animals ; Pregabalin ; Large Neutral Amino Acid-Transporter 1/genetics ; Large Neutral Amino Acid-Transporter 1/metabolism ; Amino Acids, Branched-Chain/metabolism ; Endothelial Cells/metabolism ; Spinal Cord/metabolism
Chemical Substances	Pregabalin (55JG375S6M) ; Large Neutral Amino Acid-Transporter 1 ; Amino Acids, Branched-Chain
Language	English
Publishing date	2023-01-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3151-3
ISSN	1520-6017 ; 0022-3549
ISSN (online)	1520-6017
ISSN	0022-3549
DOI	10.1016/j.xphs.2022.12.028
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Article ; Online: Involvement of GAT2/Slc6a13 in hypotaurine uptake at fetal-facing plasma membrane of syncytiotrophoblasts at mid-to-late gestation in rats and mice.

Nishimura, Tomohiro / Araki, Hikari / Higuchi, Kei / Noguchi, Saki / Saito, Kei / Hara, Kanako / Yagishita, Haruya / Akashi, Risa / Obata, Sakiko / Tomi, Masatoshi

Placenta

2024 Volume 147, Page(s) 59–67

Abstract: Introduction: Hypotaurine, a precursor to taurine, is known for its antioxidant properties and is prominently present in fetal plasma and the placenta. Our previous research revealed that ezrin-knockout mice experience fetal growth retardation, ... ...

Abstract	Introduction: Hypotaurine, a precursor to taurine, is known for its antioxidant properties and is prominently present in fetal plasma and the placenta. Our previous research revealed that ezrin-knockout mice experience fetal growth retardation, coinciding with reduced hypotaurine levels in fetal plasma. This study aims to elucidate the expression and role of hypotaurine transporters within the placenta. Methods: We employed quantitative RT-PCR to measure mRNA expression of GAT transporter family members in the placenta during mid-to-late gestation. LC/MS/MS was used to analyze the distribution of hypotaurine in different placental subregions. Immunohistochemistry was utilized to examine the localization of GAT2 in mice. Placental hypotaurine uptake from fetal circulation was studied via umbilical perfusion in rats. Results: Among hypotaurine transporters, GAT2 exhibited increased mRNA and protein expression in murine placenta during mid-to-late gestation. Notably, GAT2/Slc6a13 mRNA and hypotaurine were most concentrated in the labyrinth of murine placenta. In contrast, enzymes responsible for hypotaurine synthesis, such as cysteine dioxygenase, cysteine sulfinic acid decarboxylase, and 2-aminoethanethiol dioxygenase, showed minimal expression in the labyrinth. These findings suggest that GAT2 is a key determinant of hypotaurine levels in the placental labyrinth. Immunohistochemical examination unveiled that GAT2 was predominantly localized on the fetal-facing plasma membrane within syncytiotrophoblasts, which co-localized with ezrin. In rat umbilical perfusion experiments, the GAT2/3 and TauT inhibitor, SNAP-5114, significantly reduced hypotaurine extraction from fetal circulation to the placenta. Discussion: The results suggest that GAT2 plays a pivotal role in the concentrative uptake of hypotaurine from fetal plasma within syncytiotrophoblasts of the placenta.
MeSH term(s)	Rats ; Mice ; Pregnancy ; Female ; Animals ; Placenta/metabolism ; Tandem Mass Spectrometry ; Trophoblasts/metabolism ; Membrane Transport Proteins/metabolism ; Cell Membrane/metabolism ; Taurine/metabolism ; Taurine/pharmacology ; Taurine/analogs & derivatives ; Mice, Knockout ; RNA, Messenger/metabolism
Chemical Substances	hypotaurine (5L08GE4332) ; Membrane Transport Proteins ; Taurine (1EQV5MLY3D) ; RNA, Messenger
Language	English
Publishing date	2024-02-01
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	603951-0
ISSN	1532-3102 ; 0143-4004
ISSN (online)	1532-3102
ISSN	0143-4004
DOI	10.1016/j.placenta.2024.01.017
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Article ; Online: Breast Cancer Resistance Protein Limits Fetal Transfer of Tadalafil in Mice.

Nishimura, Tomohiro / Ishii, Mari / Tanaka, Hiroaki / Noguchi, Saki / Ikeda, Tomoaki / Tomi, Masatoshi

Journal of pharmaceutical sciences

2023 Volume 113, Issue 2, Page(s) 486–492

Abstract: Tadalafil, a phosphodiesterase 5 (PDE5) inhibitor, is a candidate therapeutic agent for fetal growth restriction and hypertensive disorders of pregnancy. In this study, we elucidated the fetal transfer of tadalafil in comparison with that of sildenafil, ... ...

Abstract	Tadalafil, a phosphodiesterase 5 (PDE5) inhibitor, is a candidate therapeutic agent for fetal growth restriction and hypertensive disorders of pregnancy. In this study, we elucidated the fetal transfer of tadalafil in comparison with that of sildenafil, the first PDE5 inhibitor to be approved. We also examined the contributions of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP) to fetal transfer. Tadalafil or sildenafil was administered to wild-type, Mdr1a/b-double-knockout or Bcrp-knockout pregnant mice by continuous infusion from gestational day (GD) 14.5 to 17.5, and the fetal-to-maternal plasma concentration ratio of unbound drug (unbound F/M ratio) was evaluated at GD 17.5. The values of unbound F/M ratio of tadalafil and sildenafil in wild-type mice were 0.80 and 1.6, respectively. The unbound F/M ratio of tadalafil was increased to 1.1 and 1.7 in Mdr1a/b-knockout and Bcrp-knockout mice, respectively, while the corresponding values for sildenafil were equal to or less than that in wild-type mice, respectively. A transcellular transport study revealed that basal-to-apical transport of both tadalafil and sildenafil was significantly higher than transport in the opposite direction in MDCKII-BCRP cells. Our research reveals that tadalafil is a newly identified substrate of human and mouse BCRP, and it appears that the fetal transfer of tadalafil is, at least in part, attributed to the involvement of BCRP within the placental processes in mice. The transfer of sildenafil to the fetus was not significantly constrained by BCRP, even though sildenafil was indeed a substantial substrate for BCRP.
MeSH term(s)	Animals ; Female ; Humans ; Mice ; Pregnancy ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics ; ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; Mice, Knockout ; Phosphodiesterase 5 Inhibitors/pharmacokinetics ; Placenta/metabolism ; Sildenafil Citrate/pharmacokinetics ; Tadalafil/pharmacokinetics ; Maternal-Fetal Exchange
Chemical Substances	ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Phosphodiesterase 5 Inhibitors ; Sildenafil Citrate (BW9B0ZE037) ; Tadalafil (742SXX0ICT) ; Abcg2 protein, mouse
Language	English
Publishing date	2023-11-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3151-3
ISSN	1520-6017 ; 0022-3549
ISSN (online)	1520-6017
ISSN	0022-3549
DOI	10.1016/j.xphs.2023.11.006
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Article ; Online: Transplacental Pharmacokinetic Model of Digoxin Based on Ex Vivo Human Placental Perfusion Study.

Kurosawa, Ken / Noguchi, Saki / Nishimura, Tomohiro / Tomi, Masatoshi / Chiba, Koji

Drug metabolism and disposition: the biological fate of chemicals

2021 Volume 50, Issue 3, Page(s) 287–298

Abstract: Digoxin is used as first-line therapy to treat fetal supraventricular tachycardia; however, because of the narrow therapeutic window, it is essential to estimate digoxin exposure in the fetus. The data from ex vivo human placental perfusion study are ... ...

Abstract	Digoxin is used as first-line therapy to treat fetal supraventricular tachycardia; however, because of the narrow therapeutic window, it is essential to estimate digoxin exposure in the fetus. The data from ex vivo human placental perfusion study are used to predict in vivo fetal exposure noninvasively, but the ex vivo fetal-to-maternal concentration (F:M) ratios observed in digoxin perfusion studies were much lower than those in vivo. In the present study, we developed a human transplacental pharmacokinetic model of digoxin using previously reported ex vivo human placental perfusion data. The model consists of maternal intervillous, fetal capillary, non-perfused tissue, and syncytiotrophoblast compartments, with multidrug resistance protein (MDR) 1 and influx transporter at the microvillous membrane (MVM) and influx and efflux transporters at the basal plasma membrane (BM). The model-predicted F:M ratio was 0.66, which is consistent with the mean in vivo value of 0.77 (95% confidence interval: 0.64-0.91). The time to achieve the steady state from the ex vivo perfusion study was estimated as 1,500 minutes, which is considerably longer than the reported ex vivo experimental durations, and this difference is considered to account for the inconsistency between ex vivo and in vivo F:M ratios. Reported digoxin concentrations in a drug-drug interaction study with MDR1 inhibitors quinidine and verapamil were consistent with the profiles simulated by our model incorporating inhibition of efflux transporter at the BM in addition to MVM. Our modeling and simulation approach should be a powerful tool to predict fetal exposure and DDIs in human placenta. SIGNIFICANCE STATEMENT: We developed a human transplacental pharmacokinetic model of digoxin based on ex vivo human placental perfusion studies in order to resolve inconsistencies between reported ex vivo and in vivo fetal-to-maternal concentration ratios. The model successfully predicted the in vivo fetal exposure to digoxin and the drug-drug interactions of digoxin and P-glycoprotein/multidrug resistance protein 1 inhibitors in human placenta.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Digoxin/pharmacokinetics ; Female ; Fetus/metabolism ; Humans ; Maternal-Fetal Exchange/physiology ; Perfusion ; Placenta/metabolism ; Pregnancy
Chemical Substances	ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Digoxin (73K4184T59)
Language	English
Publishing date	2021-12-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.121.000648
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Article ; Online: MicroRNA-126 suppresses the invasion of trophoblast-model JEG-3 cells by targeting LIN28A.

Pan, Xiaole / Noguchi, Saki / Ando, Misuzu / Nishimura, Tomohiro / Tomi, Masatoshi

Biochemical and biophysical research communications

2021 Volume 545, Page(s) 132–137

Abstract: Inadequate trophoblast invasion and impaired trophoblast-induced vascular remodeling are features of preeclampsia. In this context, an angiogenesis-related microRNA, miR-126, is abnormally expressed in preeclampsia placentas, but its role in trophoblast ... ...

Abstract	Inadequate trophoblast invasion and impaired trophoblast-induced vascular remodeling are features of preeclampsia. In this context, an angiogenesis-related microRNA, miR-126, is abnormally expressed in preeclampsia placentas, but its role in trophoblast development remains unclear. The purpose of this study was to investigate the roles of miR-126 in the proliferation, migration, and invasion processes of trophoblast cells using the human choriocarcinoma-derived JEG-3 cell line as a model. The mRNA expression profiling of JEG-3 cells with and without miR-126 overexpression, in combination with bioinformatics analysis, identified LIN28A as a putative target of miR-126. The results of real-time RT-PCR and luciferase assay were consistent with this idea. Overexpression of miR-126 in JEG-3 cells decreased the invasive ability of the cells without affecting proliferation or migration. The invasiveness of JEG-3 cells was significantly reduced to a similar extent by knockdown of LIN28A with siRNA and by miR-126-overexpression-induced downregulation of LIN28A, although the level of LIN28A protein was much lower in the siLIN28A-transfected cells. These results indicate that miR-126 suppresses JEG-3 cell invasion by targeting LIN28A, and suggest that miR-126-mediated downregulation of LIN28A might contribute to the onset/deterioration of preeclampsia.
MeSH term(s)	Cell Line, Tumor ; Cell Movement/genetics ; Cell Proliferation/genetics ; Down-Regulation ; Female ; Gene Expression Profiling ; Gene Knockdown Techniques ; Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Placenta/metabolism ; Pre-Eclampsia/genetics ; Pre-Eclampsia/metabolism ; Pre-Eclampsia/pathology ; Pregnancy ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Small Interfering/genetics ; RNA-Binding Proteins/antagonists & inhibitors ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Trophoblasts/metabolism ; Trophoblasts/pathology
Chemical Substances	Lin28A protein, human ; MIRN126 microRNA, human ; MicroRNAs ; RNA, Messenger ; RNA, Small Interfering ; RNA-Binding Proteins
Language	English
Publishing date	2021-02-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2021.01.077
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Article ; Online: Development of a Pharmacokinetic Model of Transplacental Transfer of Metformin to Predict In Vivo Fetal Exposure.

Kurosawa, Ken / Chiba, Koji / Noguchi, Saki / Nishimura, Tomohiro / Tomi, Masatoshi

Drug metabolism and disposition: the biological fate of chemicals

2020 Volume 48, Issue 12, Page(s) 1293–1302

Abstract: Two types of systems are used in ex vivo human placental perfusion studies to predict fetal drug exposures, that is, closed systems with recirculation of the maternal and fetal buffer and open systems using a single-pass mode without recirculation. The ... ...

Abstract	Two types of systems are used in ex vivo human placental perfusion studies to predict fetal drug exposures, that is, closed systems with recirculation of the maternal and fetal buffer and open systems using a single-pass mode without recirculation. The in vivo fetal/maternal (F:M) ratio of metformin, a cationic drug that crosses the placenta, is consistent with that reported in an open system ex vivo but not with that in a closed system. In the present study, we aimed to develop a pharmacokinetic (PK) model of transplacental transfer of metformin to predict in vivo fetal exposure to metformin and to resolve the apparent inconsistency between open and closed ex vivo systems. The developed model shows that the difference between open and closed systems is due to the difference in the time required to achieve the steady state. The model-predicted F:M ratio (approx. 0.88) is consistent with reported in vivo values [mean (95% confidence interval): 1.10 (0.69-1.51)]. The model incorporates bidirectional transport via organic cation transporter 3 (OCT3) at the basal plasma membrane, and simulations indicate that the use of trimethoprim (an OCT3 inhibitor) to prevent microbial growth in the placenta ex vivo has a negligible effect on the overall maternal-to-fetal and fetal-to-maternal clearances. The model could successfully predict in vivo fetal exposure using ex vivo human placental perfusion data from both closed and open systems. This transplacental PK modeling approach is expected to be useful for evaluating human fetal exposures to other poorly permeable compounds, besides metformin. SIGNIFICANCE STATEMENT: We developed a pharmacokinetic model of transplacental transfer of metformin, used to treat gestational diabetes mellitus, in order to predict in vivo fetal exposure and resolve the discrepancy between reported findings in open and closed ex vivo perfusion systems. The discrepancy is due to a difference in the time required to reach the steady state. The model can predict in vivo fetal exposure using data from both closed and open systems.
MeSH term(s)	Cell Membrane/metabolism ; Computer Simulation ; Female ; Fetus/blood supply ; Fetus/metabolism ; Humans ; Maternal-Fetal Exchange/drug effects ; Maternal-Fetal Exchange/physiology ; Metformin/pharmacokinetics ; Models, Biological ; Organic Cation Transport Proteins/antagonists & inhibitors ; Organic Cation Transport Proteins/metabolism ; Perfusion ; Placenta/blood supply ; Placenta/cytology ; Placenta/metabolism ; Pregnancy ; Trimethoprim/pharmacology
Chemical Substances	Organic Cation Transport Proteins ; solute carrier family 22 (organic cation transporter), member 3 ; Metformin (9100L32L2N) ; Trimethoprim (AN164J8Y0X)
Language	English
Publishing date	2020-10-13
Publishing country	United States
Document type	Journal Article ; Validation Study
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.120.000127
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Article ; Online: Limited Impact of Murine Placental MDR1 on Fetal Exposure of Certain Drugs Explained by Bypass Transfer Between Adjacent Syncytiotrophoblast Layers.

Fujita, Arimi / Noguchi, Saki / Hamada, Rika / Inoue, Satoko / Shimada, Tsutomu / Katakura, Satomi / Maruyama, Tetsuo / Sai, Yoshimichi / Nishimura, Tomohiro / Tomi, Masatoshi

Pharmaceutical research

2022 Volume 39, Issue 7, Page(s) 1645–1658

Abstract: Purpose: Multidrug resistance protein 1 (MDR1) is located at the interface between two syncytiotrophoblast layers in rodent placenta, and may influence fetal drug distribution. Here, we quantitatively compare the functional impact per single MDR1 ... ...

Abstract	Purpose: Multidrug resistance protein 1 (MDR1) is located at the interface between two syncytiotrophoblast layers in rodent placenta, and may influence fetal drug distribution. Here, we quantitatively compare the functional impact per single MDR1 molecule of MDR1 at the placental barrier and blood-brain barrier in mice. Methods: MDR1A and MDR1B proteins were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Paclitaxel or digoxin was continuously administered to pregnant Mdr1a Results: MDR1A and MDR1B proteins are expressed in the membrane of mouse placental labyrinth, and total MDR1 at the placental barrier amounts to about 30% of that at the blood-brain barrier. The fetal-to-maternal plasma concentration ratio of digoxin was only marginally affected in Mdr1a Conclusion: Our findings indicate that murine placental MDR1 has a minimal influence on the fetal concentration of certain substrates, such as digoxin, due to bypass transfer, probably via connexin26 gap junctions.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B/metabolism ; Animals ; Chromatography, Liquid ; Digoxin/pharmacokinetics ; Female ; Maternal Exposure ; Mice ; Paclitaxel/pharmacokinetics ; Placenta/metabolism ; Pregnancy ; Tandem Mass Spectrometry ; Trophoblasts/metabolism
Chemical Substances	ATP Binding Cassette Transporter, Subfamily B ; Digoxin (73K4184T59) ; multidrug resistance protein 3 (9EI49ZU76O) ; Abcb1b protein, mouse (EC 7.6.2.2) ; Paclitaxel (P88XT4IS4D)
Language	English
Publishing date	2022-01-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	843063-9
ISSN	1573-904X ; 0724-8741 ; 0739-0742
ISSN (online)	1573-904X
ISSN	0724-8741 ; 0739-0742
DOI	10.1007/s11095-022-03165-6
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Article ; Online: Role of Uptake Transporters OAT4, OATP2A1, and OATP1A2 in Human Placental Bio-disposition of Pravastatin.

Fokina, Valentina M / Patrikeeva, Svetlana / Wang, Xiao-Ming / Noguchi, Saki / Tomi, Masatoshi / König, Jörg / Ahmed, Mahmoud S / Nanovskaya, Tatiana

Journal of pharmaceutical sciences

2021 Volume 111, Issue 2, Page(s) 505–516

Abstract: Pravastatin is currently under evaluation for prevention of preeclampsia. Factors contributing to placental disposition of pravastatin are important in assessment of potential undesirable fetal effects. The purpose of this study was to identify the ... ...

Abstract	Pravastatin is currently under evaluation for prevention of preeclampsia. Factors contributing to placental disposition of pravastatin are important in assessment of potential undesirable fetal effects. The purpose of this study was to identify the uptake transporters that contribute to the placental disposition of pravastatin. Our data revealed the expression of organic anion transporting polypeptide 1A2 (OATP1A2) and OATP2A1 in the apical, and OATP2B1 and OATP5A1 in the basolateral membranes of the placenta, while organic anion transporter 4 (OAT4) exhibited higher expression in basolateral membrane but was detected in both membranes. Preloading placental membrane vesicles with glutarate increased the uptake of pravastatin suggesting involvement of glutarate-dependent transporters such as OAT4. In the HEK293 cells overexpressing individual uptake transporters, OATP2A1, OATP1A2 and OAT4 were determined to accept pravastatin as a substrate at physiological pH, while the uptake of pravastatin by OATP2B1 (known to interact with pravastatin at acidic pH) and OATP5A1 was not detected at pH 7.4. These findings led us to propose that OATP1A2 and OATP2A1 are responsible for the placental uptake of pravastatin from the maternal circulation, while OAT4 mediates the passage of the drug across placental basolateral membrane in the fetal-to-maternal direction.
MeSH term(s)	Biological Transport ; Female ; HEK293 Cells ; Humans ; Organic Anion Transporters/metabolism ; Placenta/metabolism ; Pravastatin/metabolism ; Pregnancy
Chemical Substances	Organic Anion Transporters ; SLCO1A2 protein, human ; Pravastatin (KXO2KT9N0G)
Language	English
Publishing date	2021-09-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3151-3
ISSN	1520-6017 ; 0022-3549
ISSN (online)	1520-6017
ISSN	0022-3549
DOI	10.1016/j.xphs.2021.09.035
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Article ; Online: Fluorouracil uptake in triple-negative breast cancer cells: Negligible contribution of equilibrative nucleoside transporters 1 and 2.

Noguchi, Saki / Takagi, Akinori / Tanaka, Takahiro / Takahashi, Yu / Pan, Xiaole / Kibayashi, Yuka / Mizokami, Ryo / Nishimura, Tomohiro / Tomi, Masatoshi

Biopharmaceutics & drug disposition

2021 Volume 42, Issue 2-3, Page(s) 85–93

Abstract: Equilibrative nucleoside transporters (ENTs) 1 and 2 reportedly accept fluorouracil as a substrate. Here, we evaluated ENT1/2 expression at the messenger RNA (mRNA), protein, and functional levels in a panel of four triple-negative breast cancer (TNBC) ... ...

Abstract	Equilibrative nucleoside transporters (ENTs) 1 and 2 reportedly accept fluorouracil as a substrate. Here, we evaluated ENT1/2 expression at the messenger RNA (mRNA), protein, and functional levels in a panel of four triple-negative breast cancer (TNBC) cell lines, BT-549, Hs578T, MDA-MB-231, and MDA-MB-435, and we examined the relationship of the observed profiles to fluorouracil sensitivity. Nitrobenzylthioinosine (NBMPR) at 0.1 μM inhibits only ENT1, while dipyridamole at 10 μM or NBMPR at 100 μM inhibits both ENT1 and ENT2. We found that the uptake of [
MeSH term(s)	Antimetabolites, Antineoplastic/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Equilibrative Nucleoside Transporter 1/genetics ; Equilibrative Nucleoside Transporter 1/metabolism ; Equilibrative-Nucleoside Transporter 2/genetics ; Equilibrative-Nucleoside Transporter 2/metabolism ; Fluorouracil/pharmacology ; Humans ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/metabolism
Chemical Substances	Antimetabolites, Antineoplastic ; Equilibrative Nucleoside Transporter 1 ; Equilibrative-Nucleoside Transporter 2 ; SLC29A1 protein, human ; SLC29A2 protein, human ; Fluorouracil (U3P01618RT)
Language	English
Publishing date	2021-02-05
Publishing country	England
Document type	Journal Article
ZDB-ID	603014-2
ISSN	1099-081X ; 0142-2782
ISSN (online)	1099-081X
ISSN	0142-2782
DOI	10.1002/bdd.2261
Database	MEDical Literature Analysis and Retrieval System OnLINE

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