scholarly journals Molecular Properties of Drugs Handled by Kidney OATs and Liver OATPs Revealed by Chemoinformatics and Machine Learning: Implications for Kidney and Liver Disease

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1720
Author(s):  
Anisha K. Nigam ◽  
Anupam A. Ojha ◽  
Julia G. Li ◽  
Da Shi ◽  
Vibha Bhatnagar ◽  
...  
Keyword(s):  
Machine Learning ◽  
Deep Learning ◽  
Kidney Disease ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Comparable Efficacy ◽  
Renal Elimination ◽  
K Nearest Neighbors ◽  
Liver Uptake ◽  
Anion Transporter

In patients with liver or kidney disease, it is especially important to consider the routes of metabolism and elimination of small-molecule pharmaceuticals. Once in the blood, numerous drugs are taken up by the liver for metabolism and/or biliary elimination, or by the kidney for renal elimination. Many common drugs are organic anions. The major liver uptake transporters for organic anion drugs are organic anion transporter polypeptides (OATP1B1 or SLCO1B1; OATP1B3 or SLCO1B3), whereas in the kidney they are organic anion transporters (OAT1 or SLC22A6; OAT3 or SLC22A8). Since these particular OATPs are overwhelmingly found in the liver but not the kidney, and these OATs are overwhelmingly found in the kidney but not liver, it is possible to use chemoinformatics, machine learning (ML) and deep learning to analyze liver OATP-transported drugs versus kidney OAT-transported drugs. Our analysis of >30 quantitative physicochemical properties of OATP- and OAT-interacting drugs revealed eight properties that in combination, indicate a high propensity for interaction with “liver” transporters versus “kidney” ones based on machine learning (e.g., random forest, k-nearest neighbors) and deep-learning classification algorithms. Liver OATPs preferred drugs with greater hydrophobicity, higher complexity, and more ringed structures whereas kidney OATs preferred more polar drugs with more carboxyl groups. The results provide a strong molecular basis for tissue-specific targeting strategies, understanding drug–drug interactions as well as drug–metabolite interactions, and suggest a strategy for how drugs with comparable efficacy might be chosen in chronic liver or kidney disease (CKD) to minimize toxicity.

scholarly journals Interactions of 172 plant extracts with human organic anion transporter 1 (SLC22A6) and 3 (SLC22A8): a study on herb-drug interactions

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e3333 ◽  
Author(s):  
Hang Lu ◽  
Zhiqiang Lu ◽  
Xue Li ◽  
Gentao Li ◽  
Yilin Qiao ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Plant Extracts ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Hek293 Cells ◽  
Pharmacokinetic Parameters ◽  
Renal Elimination ◽  
Juncus Effusus ◽  
Anion Transporter

BackgroundHerb-drug interactions (HDIs) resulting from concomitant use of herbal products with clinical drugs may cause adverse reactions. Organic anion transporter 1 (OAT1) and 3 (OAT3) are highly expressed in the kidney and play a key role in the renal elimination of substrate drugs. So far, little is known about the herbal extracts that could modulate OAT1 and OAT3 activities.MethodsHEK293 cells stably expressing human OAT1 (HEK-OAT1) and OAT3 (HEK-OAT3) were established and characterized. One hundred seventy-two extracts from 37 medicinal and economic plants were prepared. An initial concentration of 5 µg/ml for each extract was used to evaluate their effects on 6-carboxylfluorescein (6-CF) uptake in HEK-OAT1 and HEK-OAT3 cells. Concentration-dependent inhibition studies were conducted for those extracts with more than 50% inhibition to OAT1 and OAT3. The extract ofJuncus effusus, a well-known traditional Chinese medicine, was assessed for its effect on thein vivopharmacokinetic parameters of furosemide, a diuretic drug which is a known substrate of both OAT1 and OAT3.ResultsMore than 30% of the plant extracts at the concentration of 5 µg/ml showed strong inhibitory effect on the 6-CF uptake mediated by OAT1 (61 extracts) and OAT3 (55 extracts). Among them, three extracts for OAT1 and fourteen extracts for OAT3 were identified as strong inhibitors with IC50values being <5 µg/ml.Juncus effususshowed a strong inhibition to OAT3in vitro, and markedly altered thein vivopharmacokinetic parameters of furosemide in rats.ConclusionThe present study identified the potential interactions of medicinal and economic plants with human OAT1 and OAT3, which is helpful to predict and to avoid potential OAT1- and OAT3-mediated HDIs.

scholarly journals Amelioration of mercury nephrotoxicity after pharmacological manipulation of organic anion transporter 1 (Oat1) and multidrug resistance-associated protein 2 (Mrp2) with furosemide

2015 ◽  
Vol 4 (5) ◽  
pp. 1324-1332 ◽  
Author(s):  
María H. Hazelhoff ◽  
Mara S. Trebucobich ◽  
Tania R. Stoyanoff ◽  
Alberto A. Chevalier ◽  
Adriana M. Torres
Keyword(s):  
Multidrug Resistance ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Renal Elimination ◽  
Pharmacological Manipulation ◽  
Anion Transporter ◽  
Mercuric Ions

Furosemide improves HgCl2-induced tubule injury up-regulating Oat1 and Mrp2, thus increasing renal elimination of mercuric ions.

Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney

1999 ◽  
Vol 276 (1) ◽  
pp. F122-F128 ◽  
Author(s):  
Makoto Hosoyamada ◽  
Takashi Sekine ◽  
Yoshikatsu Kanai ◽  
Hitoshi Endou
Keyword(s):  
Proximal Tubule ◽  
Organic Anion ◽  
Basolateral Membrane ◽  
Human Kidney ◽  
Organic Anion Transporter ◽  
Renal Elimination ◽  
Xenopus Laevis Oocytes ◽  
Cdna Clones ◽  
Phenol Red ◽  
Anion Transporter

Recently, we isolated the multispecific organic anion transporter (OAT1) from the rat kidney, which plays important roles in the renal elimination of endogenous and exogenous organic anions including clinically important drugs. In the present study, we cloned and characterized human OAT1. Two cDNA clones, hOAT1–1 cDNA and hOAT1–2 cDNA, were isolated from a human kidney cDNA library, whose amino acid sequences were 86.0% and 87.8% identical to that of rat OAT1, respectively. When expressed in Xenopus laevis oocytes, hOAT1 mediated sodium-independent uptake of p-aminohippurate (PAH) ( K m = 9.3 ± 1.0 μM). hOAT1-mediated PAH uptake was inhibited by bulky inorganic anions, various xenobiotics, and endogenous substances, including benzylpenicillin, furosemide, indomethacin, probenecid, phenol red, urate, and α-ketoglutarate. Northern blot analysis revealed that hOAT1 mRNA is strongly expressed in human kidney; transcripts of different sizes are expressed in skeletal muscle, brain, and placenta. Immunohistochemical analysis using rabbit IgG antibody against the carboxy-terminal 14 peptides of hOAT1 revealed that hOAT1 is expressed at the basolateral membrane of the proximal tubule. hOAT1 gene was located on human chromosome 11q13.1 by fluorescent in situ hybridization analysis. These results indicate that hOAT1 is a multispecific organic anion transporter on the basolateral membrane of the proximal tubule in human kidney.

scholarly journals Oral Proteasomal Inhibitors Ixazomib, Oprozomib, and Delanzomib Upregulate the Function of Organic Anion Transporter 3 (OAT3): Implications in OAT3-Mediated Drug-Drug Interactions

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 314
Author(s):  
Yunzhou Fan ◽  
Zhengxuan Liang ◽  
Jinghui Zhang ◽  
Guofeng You
Keyword(s):  
Drug Interactions ◽  
Anticancer Agents ◽  
Organic Anion ◽  
Basolateral Membrane ◽  
Drug Efficacy ◽  
Organic Anion Transporter ◽  
Renal Elimination ◽  
Transport Activity ◽  
Anion Transporter ◽  
Organic Anion Transporter 3

Organic anion transporter 3 (OAT3) is mainly expressed at the basolateral membrane of kidney proximal tubules, and is involved in the renal elimination of various kinds of important drugs, potentially affecting drug efficacy or toxicity. Our laboratory previously reported that ubiquitin modification of OAT3 triggers the endocytosis of OAT3 from the plasma membrane to intracellular endosomes, followed by degradation. Oral anticancer drugs ixazomib, oprozomib, and delanzomib, as proteasomal inhibitors, target the ubiquitin–proteasome system in clinics. Therefore, this study investigated the effects of ixazomib, oprozomib, and delanzomib on the expression and transport activity of OAT3 and elucidated the underlying mechanisms. We showed that all three drugs significantly increased the accumulation of ubiquitinated OAT3, which was consistent with decreased intracellular 20S proteasomal activity; stimulated OAT3-mediated transport of estrone sulfate and p-aminohippuric acid; and increased OAT3 surface expression. The enhanced transport activity and OAT3 expression following drug treatment resulted from an increase in maximum transport velocity of OAT3 without altering the substrate binding affinity, and from a decreased OAT3 degradation. Together, our study discovered a novel role of anticancer agents ixazomib, oprozomib, and delanzomib in upregulating OAT3 function, unveiled the proteasome as a promising target for OAT3 regulation, and provided implication of OAT3-mediated drug–drug interactions, which should be warned against during combination therapies with proteasome inhibitor drugs.

Characterization of hepatobiliary organic anion transporter regulation in the Zucker rat

2004 ◽  
Vol 42 (08) ◽  
Author(s):  
A Geier ◽  
CG Dietrich ◽  
C Gartung ◽  
F Lammert ◽  
HE Wasmuth ◽  
...  
Keyword(s):  
Organic Anion ◽  
Organic Anion Transporter ◽  
Zucker Rat ◽  
Anion Transporter
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