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

Anisha K Nigam,Anupam A Ojha,Julia G Li,Kabir B Nigam,Ruben Abagyan,Vibha Bhatnagar,Sanjay K Nigam,Da Shi

doi:10.3390/pharmaceutics13101720

Anisha K Nigam, Anupam A Ojha + Show 6 more

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https://doi.org/10.3390/pharmaceutics13101720

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Abstract

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.

Highlights

A major issue in patients with impaired liver or kidney function is the route of elimination of prescribed drugs
Several hepatic and renal transporters can interact with organic anion drugs, four primary organic anion transporters involved in drug handling that have been initially highlighted by regulatory agencies are predominantly hepatic members of the OATP (SLCO) family and the predominantly renal members of the OAT (SLC22) family of solute carriers [16]
In the case of liver, entry often occurs via the major multi-specific drug transporters: the organic anion transporting polypeptides, OATP1B1 (SLCO1B1) or OATP1B3 (SLCO1B3), grouped below as the main “liver” organic anion uptake transporters

Summary

Introduction

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]. Several hepatic and renal transporters can interact with organic anion drugs, four primary organic anion transporters involved in drug handling that have been initially highlighted by regulatory agencies are predominantly hepatic members of the OATP (SLCO) family and the predominantly renal members of the OAT (SLC22) family of solute carriers [16].

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