Regulation of organic anion transporters: Role in physiology, pathophysiology, and drug elimination

Zhang, Jinghui; Wang, Haoxun; Fan, Yunzhou; Yu, Zhou; You, Guofeng

doi:10.1016/j.pharmthera.2020.107647

Cited by 54 publications

(46 citation statements)

References 190 publications

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“…A major issue in patients with impaired liver or kidney function is the route of elimination of prescribed drugs. Many common drugs such as beta-lactam antibiotics (e.g., penicillin), antivirals (e.g., tenofovir), analgesics (e.g., ibuprofen), statins used for hypercholesterolemia (e.g., pravastatin), antihypertensives (e.g., hydrochlorothiazide), and chemotherapeutics (e.g., methotrexate) are small organic anions [ 1 , 2 , 3 , 4 , 5 , 6 ]. Upon entering the blood through oral or parenteral routes, they are frequently taken up by the liver, where they may be modified by drug metabolizing enzymes (DMEs).…”

Section: Introductionmentioning

confidence: 99%

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

Nigam

Ojha

et al. 2021

Pharmaceutics

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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.

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Section: Introductionmentioning

confidence: 99%

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

Nigam

Ojha

et al. 2021

Pharmaceutics

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“…The transporters OAT1/3 belong to the Solute Carrier Family 22 (SLC22) (23,24). They are distributed in many tissues, but mainly act in the kidney (25). In the kidney, they are expressed in the basal lateral membrane of renal tubular epithelial cells (26,27), which promote the uptake of MTX from blood into renal tubular epithelial cells and mediate the urine excretion of MTX (28,29).…”

Section: Discussionmentioning

confidence: 99%

Wuzhi capsule increased systemic exposure to methotrexate by inhibiting the expression of OAT1/3 and P-gp

Fu¹,

Wang²,

Guo³

et al. 2021

Ann Transl Med

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Background: Methotrexate (MTX) is an important anticancer agent and immunosuppressant with a narrow therapeutic window. Wuzhi capsule (WZC) is an extract of Schisandra which is widely used to treat liver diseases. Co-administration of MTX and WZC is common in the clinical setting, but research on the interaction between WZC and MTX is limited. This study aimed to investigate the effects of WZC on the pharmacokinetics of MTX in rats and to explore the role of membrane transport proteins OAT1/3 and P-gp in the interaction of these drugs.Methods: Plasma MTX concentration was detected by ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS), and the messenger RNA (mRNA) and protein expression of OAT1/3 and P-gp was evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting analyses, respectively. Results:The study results revealed that co-administration of WZC decreased the CL z/F and V z/F of MTX, increased the C max and area under the curve [(AUC) 0-24 h ] of MTX, and inhibited OAT1/3 expression in the kidney and P-gp expression in the small intestine. Conclusions:The findings suggested that there is a drug interaction between WZC and MTX and that OAT1/3 in the kidney and P-gp in the small intestine may be the main targets mediating the drug interaction, and attention should be paid when they are used in combination.

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“…Organic anion transporters (OATs) are a group of transmembrane proteins specifically expressed at cellular barriers in multiple tissues, such as kidney, liver, intestine, placenta, brain, retina, and olfactory mucosa [1][2][3][4]. OATs play essential roles in mediating organic anion molecules across cell membranes, including a wide range of endogenous and exogenous molecules such as toxins and therapeutic drugs.…”

Section: Introductionmentioning

confidence: 99%

“…OATs play essential roles in mediating organic anion molecules across cell membranes, including a wide range of endogenous and exogenous molecules such as toxins and therapeutic drugs. Therefore, OATs are significant players in pharmacological responses including drug absorption, distribution, metabolism, and elimination [3,[5][6][7][8][9]. Several animal and clinical studies have been reported on the relationship between kidney diseases and renal OATs [3,6].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, OATs are significant players in pharmacological responses including drug absorption, distribution, metabolism, and elimination [3,[5][6][7][8][9]. Several animal and clinical studies have been reported on the relationship between kidney diseases and renal OATs [3,6]. While kidney diseases could directly affect the function and expression of renal OATs, damage to renal OATs could also alter various renal functions, leading to kidney disease progression [6].…”

Section: Introductionmentioning

confidence: 99%

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Protein kinase C regulates organic anion transporter 1 through phosphorylating ubiquitin ligase Nedd4–2

Liu

Zhang

et al. 2021

BMC Mol and Cell Biol

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Background Organic anion transporter 1 (OAT1) is a drug transporter expressed on the basolateral membrane of the proximal tubule cells in kidneys. It plays an essential role in the disposition of numerous clinical therapeutics, impacting their pharmacological and toxicological properties. The activation of protein kinase C (PKC) is shown to facilitate OAT1 internalization from cell surface to intracellular compartments and thereby reducing cell surface expression and transport activity of the transporter. The PKC-regulated OAT1 internalization occurs through ubiquitination, a process catalyzed by a E3 ubiquitin ligase, neural precursor cell expressed developmentally down-regulated 4–2 (Nedd4–2). Nedd4–2 directly interacts with OAT1 and affects ubiquitination, expression and stability of the transporter. However, whether Nedd4–2 is a direct substrate for PKC-induced phosphorylation is unknown. Results In this study, we investigated the role of Nedd4–2 phosphorylation in the PKC regulation of OAT1. The results showed that PKC activation enhanced the phosphorylation of Nedd4–2 and increased the OAT1 ubiquitination, which was accompanied by a decreased OAT1 cell surface expression and transport function. And the effects of PKC could be reversed by PKC-specific inhibitor staurosporine. We further discovered that the quadruple mutant (T197A/S221A/S354A/S420A) of Nedd4–2 partially blocked the effects of PKC on Nedd4–2 phosphorylation and on OAT1 transport activity. Conclusions Our investigation demonstrates that PKC regulates OAT1 likely through direct phosphorylation of Nedd4–2. And four phosphorylation sites (T197, S221, S354, and S420) of Nedd4–2 in combination play an important role in this regulatory process.

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Regulation of organic anion transporters: Role in physiology, pathophysiology, and drug elimination

Cited by 54 publications

References 190 publications

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

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

Wuzhi capsule increased systemic exposure to methotrexate by inhibiting the expression of OAT1/3 and P-gp

Protein kinase C regulates organic anion transporter 1 through phosphorylating ubiquitin ligase Nedd4–2

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