Article
Chemistry, Medicinal
Youmna Ali, Tahiatul Shams, Zhengqi Cheng, Yue Li, Chelsea Siu-Wai Chun, Wenying Shu, Xiaofeng Bao, Ling Zhu, Michael Murray, Fanfan Zhou
Summary: This study evaluated the regulatory actions of Wnt inhibitors on human renal Organic anion transporters and Organic anion transporting polypeptides, showing that these inhibitors significantly decrease the activities and membrane expression of multiple transporters. The findings suggest that Wnt inhibitors may have unexpected effects on drug entry into cells.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Chunxu Ni, Xuyang Wang, Jie Chen, Su Xu, Wenjing Ye, Mei Hong
Summary: In this study, it was found that the leucine heptad repeats within the transmembrane domains of OATP1B1 play crucial roles in its function and protein-protein interactions, with disruption of the repeats in TM3 significantly reducing OATP1B1's uptake function.
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
(2021)
Article
Biochemistry & Molecular Biology
Arun Kumar Tonduru, Santosh Kumar Adla, Kristiina M. M. Huttunen, Thales Kronenberger, Antti Poso
Summary: In this study, a comprehensive structural dataset of organic anion transporting polypeptides (OATPs) was generated using a combination of homology modeling and molecular dynamics simulations. The models revealed a conserved transmembrane helix folding and an inner pore shaped binding pocket. Simulation results indicated the importance of salt bridges between TM1 and TM7, as well as interactions between TM1 and TM4, in substrate transport.
Article
Biochemistry & Molecular Biology
Santosh Kumar Adla, Arun Kumar Tonduru, Thales Kronenberger, Eva Kudova, Antti Poso, Kristiina M. Huttunen
Summary: In this study, synthetic neurosteroids were delivered into MCF-7 cells via OATPs to investigate structural components necessary for cellular uptake and understand brain drug delivery. The research identified key structural features that improve the affinity of neurosteroids and interact with specific amino acids, providing insights for potential drug delivery strategies across the blood-brain barrier.
Article
Entomology
Janin Roesner, Johanne Tietmeyer, Hans Merzendorfer
Summary: This study identified highly expressed OATP genes in relevant tissues of the red flour beetle, Tribolium castaneum, and showed their involvement in insecticide tolerance through RNAi experiments. The upregulation of certain genes in response to insecticide treatment and increased mortalities after gene silencing suggest the role of OATPs in insecticide resistance, highlighting the importance of studying these transporters in agricultural and forestry practices.
JOURNAL OF PEST SCIENCE
(2021)
Review
Biochemistry & Molecular Biology
Kelsy L. Nilles, Erica I. Williams, Robert D. Betterton, Thomas P. Davis, Patrick T. Ronaldson
Summary: Stroke is a major cause of death and disability worldwide. Despite successful identification of neuroprotective agents in preclinical stroke studies, none of these drugs have advanced beyond phase III clinical trials. One reason for these failures is the lack of consideration of blood-brain barrier (BBB) transport mechanisms. This review discusses specific BBB uptake transporters that can be targeted to improve neuroprotective drug delivery and presents perspectives on integrating transporter pharmacology into preclinical stroke research. Considerations such as species selection and co-morbid conditions are also discussed to optimize translational success.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Renata Pavlic, Suzana Vidic, Maja Anko, Tamara Knific, Tomaz Buedefeld, Kristina Marton, Masa Sinreih, Stefan Poschner, Walter Jaeger, Snjezana Frkovic-Grazio, Tea Lanisnik Rizner
Summary: Endometrial cancer is associated with increased estrogen actions, which can be formed from estrone-sulphate through various transporters. Higher levels of OATPs and down-regulation of ABCG2 and SLC51B were observed in EC tissue. The transporter SLCO1B3 may play a crucial role in E1-S uptake in tumors without lymphovascular invasion.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biology
Jasia King, Sangita Swapnasrita, Roman Truckenmuller, Stefan Giselbrecht, Rosalinde Masereeuw, Aurelie Carlier
Summary: The study explores the use of mathematical models to compare two types of active transport kinetics in the bioartificial kidney, with results indicating that transporter density is the most influential parameter for the clearance of indoxyl sulfate (IS). Furthermore, a uniform distribution of transporters in the device improves IS clearance, emphasizing the importance of a high-quality, functional proximal tubule monolayer in the bioartificial kidney.
COMPUTERS IN BIOLOGY AND MEDICINE
(2021)
Review
Biochemistry & Molecular Biology
Pedro Caetano-Pinto, Simone H. Stahl
Summary: Organic anion transporters 1 and 3 (OAT1 and OAT3) are crucial for kidney function and play a role in regulating the secretion of small molecules and toxic by-products. Understanding the regulatory mechanisms of these transporters can aid in drug development.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Environmental Sciences
Ruirui Zhang, Xin Li, Zhaoxin Su, Fangyuan Ning, Yuxue Gao
Summary: In this study, the effect of dietary antioxidants on the excretion of PFOA was investigated in mice. It was found that BHT increased urinary excretion of PFOA while TP decreased it. Mechanistic investigation revealed that BHT enhanced renal reabsorption of PFOA through increased expression of Oatp1a1, and αT increased fecal excretion of PFOA by reducing intestinal permeability.
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
(2023)
Article
Chemistry, Organic
Sribash Das, Rama Karn, Mohit Kumar, Soumya Srimayee, Debasis Manna
Summary: A molecular switch has been developed that can recognize and transport Cl- across lipid bilayers. The conformational changes induced by Cl- were confirmed through XRD-crystal structure and NOESY NMR spectra studies. The transportation of H+/Cl- across membranes was achieved through cooperative interactions between the quinazoline moiety and the thiourea moiety. The potent compound also exhibited increased Cl- transport in acidic environments and showed antibacterial activities by transporting H+/Cl- across Gram-positive bacteria.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Article
Medicine, Research & Experimental
Christine C. Orozco, Mikko Neuvonen, Yi-An Bi, Matthew A. Cerny, Sumathy Mathialagan, Laurie Tylaska, Brian Rago, Chester Costales, Amanda King-Ahmad, Mikko Niemi, A. David Rodrigues
Summary: This study found that sulfated bile acids (BA-S) can potentially serve as clinical biomarkers for OATP1B1/3. The BA-S substrates were observed in OATP1B1, OATP1B3, and NTCP transfected into human embryonic kidney 293 cells, with minimal uptake in other solute carriers (SLCs). Inhibition of BA-S uptake in human hepatocytes was greater with rifampicin (OATP1B1/3 selective inhibitor) than other inhibitors.
MOLECULAR PHARMACEUTICS
(2023)
Article
Pharmacology & Pharmacy
Arne Gessner, Fabian Mueller, Pia Wenisch, Markus R. R. Heinrich, Joerg Koenig, Peter Stopfer, Martin F. F. Fromm
Summary: This study examines the sensitivity and specificity of endogenous biomarkers as tools for detecting drug-drug interactions mediated by renal transport proteins. Choline and trimethylamine N-oxide are identified as sensitive and specific biomarkers for OCT2/MATEs, while indoleacetyl glutamine and indoleacetic acid are found to be sensitive and specific biomarkers for renal OATs.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2023)
Article
Chemistry, Medicinal
Katherine D. Lynch, Michelle L. Montonye, Dan-Dan Tian, Tarana Arman, Victoria O. Oyanna, Baron J. Bechtold, Tyler N. Graf, Nicholas H. Oberlies, Mary F. Paine, John D. Clarke
Summary: Silymarin, derived from milk thistle seeds, contains flavonolignans that are substrates for OATPs/Oatps. Research shows that OATPs/Oatps play a role in flavonolignan cellular uptake, and mediate interactions between silymarin and diseases like NASH on drug exposure.
PHYTOTHERAPY RESEARCH
(2021)
Article
Multidisciplinary Sciences
Alexander M. Gilchrist, Xin Wu, Bryson A. Hawkins, David E. Hibbs, Philip A. Gale
Summary: Synthetic anion transporters have potential in treating life-threatening diseases and fluorination has been shown to tune their properties. In this study, a series of fluorinated tetrapodal anion transporters were designed and their effects on lipophilicity, solubility, deliverability, and anion transport selectivity were investigated. The most fluorinated tetrathiourea displayed the highest transport activity and an interesting inversion of Cl- vs NO3- transport selectivity was observed.
Article
Pharmacology & Pharmacy
Wooin Lee, Satoshi Koyama, Kiyoe Morita, Aya Kiriake, Ryota Kikuchi, Xiaoyan Chu, Nora Lee, Renato J. Scialis, Hong Shen, Emi Kimoto, Larry Tremaine, Naoki Ishiguro, Ralf Lotz, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama
Article
Pharmacology & Pharmacy
Kazuyoshi Michiba, Kazuya Maeda, Ko Kurimori, Tsuyoshi Enomoto, Osamu Shimomura, Tomoyo Takeuchi, Hiroyuki Nishiyama, Tatsuya Oda, Hiroyuki Kusuhara
Summary: This study characterized the functions of major intestinal uptake/efflux drug transporters in freshly isolated human jejunum sections using the Ussing chamber system. The findings showed a good correlation between the mucosal-to-serosal apparent permeability coefficient of various drugs and reported human FaFg values, highlighting the importance of intestinal uptake transporters in facilitating drug absorption in humans.
DRUG METABOLISM AND DISPOSITION
(2021)
Review
Pharmacology & Pharmacy
Tatsuki Mochizuki, Tadahaya Mizuno, Kazuya Maeda, Hiroyuki Kusuhara
Summary: Drug transporters play crucial roles in eliminating compounds from the blood, with genetic variation and drug-drug interactions being underlying factors for pharmacokinetic differences of transporter substrates. Some endogenous substrates of drug transporters have been identified as biomarkers to assess transporter activity differences. Metabolomic analysis is a promising approach for identifying endogenous substrates through metabolites.
DRUG METABOLISM AND PHARMACOKINETICS
(2021)
Article
Chemistry, Medicinal
Takashi Yoshikado, Wooin Lee, Kota Toshimoto, Kiyoe Morita, Aya Kiriake, Xiaoyan Chu, Nora Lee, Emi Kimoto, Manthena V. S. Varma, Ryota Kikuchi, Renato J. Scialis, Hong Shen, Naoki Ishiguro, Ralf Lotz, Albert P. Li, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama
Summary: Hepatic uptake clearances of OATP1B substrates were compared between plated human hepatocytes (PHH) and suspended human hepatocytes (SHH), showing differences in uptake kinetics and cell-to-medium concentration ratios. PHH is useful for high-throughput evaluation of hepatic uptake/efflux clearances and Kp,Kuu, with caution needed for hydrophilic drugs with low uptake/cellular binding.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2021)
Article
Cell & Tissue Engineering
Shinpei Yoshida, Takayuki Honjo, Keita Iino, Ryunosuke Ishibe, Sylvia Leo, Tomoka Shimada, Teruhiko Watanabe, Masaya Ishikawa, Kazuya Maeda, Hiroyuki Kusuhara, Nobuaki Shiraki, Shoen Kume
Summary: This study aimed to generate matured small intestinal cells mimicking human small intestine from human-induced pluripotent stem cells (iPSCs). By culturing iPSC-derived intestinal progenitor cells on collagen vitrigel membrane and treating with a simple maturation medium, enterocyte-like cells were successfully generated, showing potential applications in drug transport and metabolism studies.
Review
Pharmacology & Pharmacy
Kazuya Maeda, Akihiro Hisaka, Kiyomi Ito, Yoshiyuki Ohno, Akihiro Ishiguro, Reiko Sato, Naomi Nagai
Summary: This review highlights the importance of clinical drug interaction studies during new drug development and introduces the general procedures proposed in a recently updated Japanese guideline. Drugs are classified based on their clearance pathway and potential intensity according to systematic reviews of the literature, which is useful for managing drug interactions in clinical practice.
DRUG METABOLISM AND PHARMACOKINETICS
(2021)
Article
Materials Science, Biomaterials
Sayaka Deguchi, Masahiro Tsuda, Kaori Kosugi, Ayaka Sakamoto, Natsumi Mimura, Ryosuke Negoro, Emi Sano, Takuro Nobe, Kazuya Maeda, Hiroyuki Kusuhara, Hiroyuki Mizuguchi, Fumiyoshi Yamashita, Yu-suke Torisawa, Kazuo Takayama
Summary: The study evaluated drug absorption to the PDMS device and investigated the drug responsiveness of human hepatocytes cultured in the PDMS device. The absorption rates of different compounds to the PDMS device were measured and found to be correlated with their octanol/water distribution coefficient values. Furthermore, the hepatocyte-chips were used to examine the response to drugs typically used to evaluate hepatic functions.
ACS BIOMATERIALS SCIENCE & ENGINEERING
(2021)
Article
Pharmacology & Pharmacy
Kazuyoshi Michiba, Kazuya Maeda, Osamu Shimomura, Yoshihiro Miyazaki, Shinji Hashimoto, Tatsuya Oda, Hiroyuki Kusuhara
Summary: This study has demonstrated the usefulness of human jejunal spheroid-derived differentiated intestinal epithelial cells as an in vitro model for studying the impact of intestinal drug-metabolizing enzymes and transporters on substrate drugs' absorption in humans. The model was able to maintain the functions of major intestinal drug-metabolizing enzymes and transporters. It could be used for quantitative evaluation of the impact of these enzymes and transporters on drug absorption.
DRUG METABOLISM AND DISPOSITION
(2022)
Review
Pharmacology & Pharmacy
Yoshiki Hashimoto, Kazuyoshi Michiba, Kazuya Maeda, Hiroyuki Kusuhara
Summary: Efflux transport systems play a crucial role in inhibiting the absorption and distribution of drugs in the human body, with genetic variations and coadministered drugs affecting transporter expression and function. Utilizing in vitro experimental tools and mathematical modeling allows for accurate prediction of drug pharmacokinetics.
JOURNAL OF PHARMACOLOGICAL SCIENCES
(2022)
Article
Oncology
Jing Jing, Yuan Chen, Luna Musib, Jin Y. Jin, Kit Wun Kathy Cheung, Kenta Yoshida, Rucha Sane
Summary: This study developed a fit-for-purpose PBPK model to assess the clinical DDIs for Ipatasertib and provide dosing strategies for the concurrent use of other CYP3A4 perpetrators or victims.
CANCER CHEMOTHERAPY AND PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Tatsuki Mochizuki, Maciej J. Zamek-Gliszczynski, Kenta Yoshida, Jialin Mao, Kunal Taskar, Hideki Hirabayashi, Xiaoyan Chu, Yurong Lai, Tadayuki Takashima, Kevin Rockich, Yoshiyuki Yamaura, Kaku Fujiwara, Tadahaya Mizuno, Kazuya Maeda, Kenichi Furihata, Yuichi Sugiyama, Hiroyuki Kusuhara
Summary: This study assessed the quantitative performance of endogenous biomarkers for OATP1B1/1B3-mediated drug-drug interactions, with CP-I's AUCR and CmaxR showing high correlation with CysA AUC. The findings provide valuable information for accurate DDI predictions and enhance understanding of interindividual variability in DDI magnitude.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Medicine, Research & Experimental
Tatsuki Mochizuki, Yasunori Aoki, Takashi Yoshikado, Kenta Yoshida, Yurong Lai, Hideki Hirabayashi, Yoshiyuki Yamaura, Kevin Rockich, Kunal Taskar, Tadayuki Takashima, Xiaoyan Chu, Maciej J. Zamek-Gliszczynski, Jialin Mao, Kazuya Maeda, Kenichi Furihata, Yuichi Sugiyama, Hiroyuki Kusuhara
Summary: In this study, a physiologically-based pharmacokinetic (PBPK) model analysis was performed to interpret clinical drug-drug interaction (DDI) data, and the results suggest that PBPK model analysis of CP-I is a promising translational approach to predict OATP1B-mediated DDIs in drug development.
CTS-CLINICAL AND TRANSLATIONAL SCIENCE
(2022)
Article
Oncology
Naoki Kotani, Justin J. Wilkins, Janet R. Wade, Steve Dang, Dhruvitkumar S. Sutaria, Kenta Yoshida, Sameer Sundrani, Hao Ding, Josep Garcia, Heather Hinton, Rucha Sane, Pascal Chanu
Summary: This study evaluated the efficacy and safety of ipatasertib, a selective AKT kinase inhibitor, in patients with metastatic castration-resistant prostate cancer. The results showed a significant correlation between ipatasertib exposure and improved survival, as well as an increased risk of adverse events with ipatasertib treatment and/or increased exposure. Despite variability in exposure, patients receiving ipatasertib treatment may continue to benefit from this therapy.
CANCER CHEMOTHERAPY AND PHARMACOLOGY
(2022)
Article
Gastroenterology & Hepatology
Chin Wong, Ajit Dash, Jill Fredrickson, Nicholas Lewin-Koh, Shan Chen, Kenta Yoshida, Yanqiu Liu, Johnny Gutierrez, Rebecca Kunder
Summary: BFKB8488A is well tolerated in patients with T2DM or NAFLD and has beneficial effects on triglyceride, HDL, and markers of liver health for both populations, with marked reduction in liver fat for patients with NAFLD.