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

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....

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Autores principales: Nigam, Anisha K., Ojha, Anupam A., Li, Julia G., Shi, Da, Bhatnagar, Vibha, Nigam, Kabir B., Abagyan, Ruben, Nigam, Sanjay K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8538396/
https://www.ncbi.nlm.nih.gov/pubmed/34684013
http://dx.doi.org/10.3390/pharmaceutics13101720
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author Nigam, Anisha K.
Ojha, Anupam A.
Li, Julia G.
Shi, Da
Bhatnagar, Vibha
Nigam, Kabir B.
Abagyan, Ruben
Nigam, Sanjay K.
author_facet Nigam, Anisha K.
Ojha, Anupam A.
Li, Julia G.
Shi, Da
Bhatnagar, Vibha
Nigam, Kabir B.
Abagyan, Ruben
Nigam, Sanjay K.
author_sort Nigam, Anisha K.
collection PubMed
description 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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spelling pubmed-85383962021-10-24 Molecular Properties of Drugs Handled by Kidney OATs and Liver OATPs Revealed by Chemoinformatics and Machine Learning: Implications for Kidney and Liver Disease Nigam, Anisha K. Ojha, Anupam A. Li, Julia G. Shi, Da Bhatnagar, Vibha Nigam, Kabir B. Abagyan, Ruben Nigam, Sanjay K. Pharmaceutics Article 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. MDPI 2021-10-18 /pmc/articles/PMC8538396/ /pubmed/34684013 http://dx.doi.org/10.3390/pharmaceutics13101720 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nigam, Anisha K.
Ojha, Anupam A.
Li, Julia G.
Shi, Da
Bhatnagar, Vibha
Nigam, Kabir B.
Abagyan, Ruben
Nigam, Sanjay K.
Molecular Properties of Drugs Handled by Kidney OATs and Liver OATPs Revealed by Chemoinformatics and Machine Learning: Implications for Kidney and Liver Disease
title Molecular Properties of Drugs Handled by Kidney OATs and Liver OATPs Revealed by Chemoinformatics and Machine Learning: Implications for Kidney and Liver Disease
title_full Molecular Properties of Drugs Handled by Kidney OATs and Liver OATPs Revealed by Chemoinformatics and Machine Learning: Implications for Kidney and Liver Disease
title_fullStr Molecular Properties of Drugs Handled by Kidney OATs and Liver OATPs Revealed by Chemoinformatics and Machine Learning: Implications for Kidney and Liver Disease
title_full_unstemmed Molecular Properties of Drugs Handled by Kidney OATs and Liver OATPs Revealed by Chemoinformatics and Machine Learning: Implications for Kidney and Liver Disease
title_short Molecular Properties of Drugs Handled by Kidney OATs and Liver OATPs Revealed by Chemoinformatics and Machine Learning: Implications for Kidney and Liver Disease
title_sort molecular properties of drugs handled by kidney oats and liver oatps revealed by chemoinformatics and machine learning: implications for kidney and liver disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8538396/
https://www.ncbi.nlm.nih.gov/pubmed/34684013
http://dx.doi.org/10.3390/pharmaceutics13101720
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