Substrate-Dependent Inhibition of the Human Organic Cation Transporter OCT2: A Comparison of Metformin with Experimental Substrates
The importance of the organic cation transporter OCT2 in the renal excretion of cationic drugs raises the possibility of drug-drug interactions (DDIs) in which an inhibitor (perpetrator) drug decreases OCT2-dependent renal clearance of a victim (substrate) drug. In fact, there are clinically signifi...
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| Published in | PloS one Vol. 10; no. 9; p. e0136451 |
|---|---|
| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Public Library of Science
01.09.2015
Public Library of Science (PLoS) |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1932-6203 1932-6203 |
| DOI | 10.1371/journal.pone.0136451 |
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| Abstract | The importance of the organic cation transporter OCT2 in the renal excretion of cationic drugs raises the possibility of drug-drug interactions (DDIs) in which an inhibitor (perpetrator) drug decreases OCT2-dependent renal clearance of a victim (substrate) drug. In fact, there are clinically significant interactions for drugs that are known substrates of OCT2 such as metformin. To identify drugs as inhibitors for OCT2, individual drugs or entire drug libraries have been investigated in vitro by using experimental probe substrates such as 1-methyl-4-phenylpyridinium (MPP+) or 4-4-dimethylaminostyryl-N-methylpyridinium (ASP+). It has been questioned whether the inhibition data obtained with an experimental probe substrate such as MPP+ or ASP+ might be used to predict the inhibition against other, clinical relevant substrates such as metformin. Here we compared the OCT2 inhibition profile data for the substrates metformin, MPP+ and ASP+. We used human embryonic kidney (HEK 293) cells stably overexpressing human OCT2 as the test system to screen 125 frequently prescribed drugs as inhibitors of OCT2-mediated metformin and MPP+ uptake. Data on inhibition of OCT2-mediated ASP+ uptake were obtained from previous literature. A moderate correlation between the inhibition of OCT2-mediated MPP+, ASP+, and metformin uptake was observed (pairwise rs between 0.27 and 0.48, all P < 0.05). Of note, the correlation in the inhibition profile between structurally similar substrates such as MPP+ and ASP+ (Tanimoto similarity T = 0.28) was even lower (rs = 0.27) than the correlation between structurally distinct substrates, such as ASP+ and metformin (T = 0.01; rs = 0.48) or MPP+ and metformin (T = 0.01; rs = 0.40). We identified selective as well as universal OCT2 inhibitors, which inhibited transport by more than 50% of one substrate only or of all substrates, respectively. Our data suggest that the predictive value for drug-drug interactions using experimental substrates rather than the specific victim drug is limited. |
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| AbstractList | The importance of the organic cation transporter OCT2 in the renal excretion of cationic drugs raises the possibility of drug-drug interactions (DDIs) in which an inhibitor (perpetrator) drug decreases OCT2-dependent renal clearance of a victim (substrate) drug. In fact, there are clinically significant interactions for drugs that are known substrates of OCT2 such as metformin. To identify drugs as inhibitors for OCT2, individual drugs or entire drug libraries have been investigated in vitro by using experimental probe substrates such as 1-methyl-4-phenylpyridinium (MPP.sup.+) or 4-4-dimethylaminostyryl-N-methylpyridinium (ASP.sup.+). It has been questioned whether the inhibition data obtained with an experimental probe substrate such as MPP.sup.+ or ASP.sup.+ might be used to predict the inhibition against other, clinical relevant substrates such as metformin. Here we compared the OCT2 inhibition profile data for the substrates metformin, MPP.sup.+ and ASP.sup.+ . We used human embryonic kidney (HEK 293) cells stably overexpressing human OCT2 as the test system to screen 125 frequently prescribed drugs as inhibitors of OCT2-mediated metformin and MPP.sup.+ uptake. Data on inhibition of OCT2-mediated ASP.sup.+ uptake were obtained from previous literature. A moderate correlation between the inhibition of OCT2-mediated MPP.sup.+, ASP.sup.+, and metformin uptake was observed (pairwise r.sub.s between 0.27 and 0.48, all P < 0.05). Of note, the correlation in the inhibition profile between structurally similar substrates such as MPP.sup.+ and ASP.sup.+ (Tanimoto similarity T = 0.28) was even lower (r.sub.s = 0.27) than the correlation between structurally distinct substrates, such as ASP.sup.+ and metformin (T = 0.01; r.sub.s = 0.48) or MPP.sup.+ and metformin (T = 0.01; r.sub.s = 0.40). We identified selective as well as universal OCT2 inhibitors, which inhibited transport by more than 50% of one substrate only or of all substrates, respectively. Our data suggest that the predictive value for drug-drug interactions using experimental substrates rather than the specific victim drug is limited. The importance of the organic cation transporter OCT2 in the renal excretion of cationic drugs raises the possibility of drug-drug interactions (DDIs) in which an inhibitor (perpetrator) drug decreases OCT2-dependent renal clearance of a victim (substrate) drug. In fact, there are clinically significant interactions for drugs that are known substrates of OCT2 such as metformin. To identify drugs as inhibitors for OCT2, individual drugs or entire drug libraries have been investigated in vitro by using experimental probe substrates such as 1-methyl-4-phenylpyridinium (MPP + ) or 4–4-dimethylaminostyryl-N-methylpyridinium (ASP + ). It has been questioned whether the inhibition data obtained with an experimental probe substrate such as MPP + or ASP + might be used to predict the inhibition against other, clinical relevant substrates such as metformin. Here we compared the OCT2 inhibition profile data for the substrates metformin, MPP + and ASP + . We used human embryonic kidney (HEK 293) cells stably overexpressing human OCT2 as the test system to screen 125 frequently prescribed drugs as inhibitors of OCT2-mediated metformin and MPP + uptake. Data on inhibition of OCT2-mediated ASP + uptake were obtained from previous literature. A moderate correlation between the inhibition of OCT2-mediated MPP + , ASP + , and metformin uptake was observed (pairwise r s between 0.27 and 0.48, all P < 0.05). Of note, the correlation in the inhibition profile between structurally similar substrates such as MPP + and ASP + (Tanimoto similarity T = 0.28) was even lower ( r s = 0.27) than the correlation between structurally distinct substrates, such as ASP + and metformin ( T = 0.01; r s = 0.48) or MPP + and metformin ( T = 0.01; r s = 0.40). We identified selective as well as universal OCT2 inhibitors, which inhibited transport by more than 50% of one substrate only or of all substrates, respectively. Our data suggest that the predictive value for drug-drug interactions using experimental substrates rather than the specific victim drug is limited. The importance of the organic cation transporter OCT2 in the renal excretion of cationic drugs raises the possibility of drug-drug interactions (DDIs) in which an inhibitor (perpetrator) drug decreases OCT2-dependent renal clearance of a victim (substrate) drug. In fact, there are clinically significant interactions for drugs that are known substrates of OCT2 such as metformin. To identify drugs as inhibitors for OCT2, individual drugs or entire drug libraries have been investigated in vitro by using experimental probe substrates such as 1-methyl-4-phenylpyridinium (MPP+) or 4–4-dimethylaminostyryl-N-methylpyridinium (ASP+). It has been questioned whether the inhibition data obtained with an experimental probe substrate such as MPP+ or ASP+ might be used to predict the inhibition against other, clinical relevant substrates such as metformin. Here we compared the OCT2 inhibition profile data for the substrates metformin, MPP+ and ASP+. We used human embryonic kidney (HEK 293) cells stably overexpressing human OCT2 as the test system to screen 125 frequently prescribed drugs as inhibitors of OCT2-mediated metformin and MPP+ uptake. Data on inhibition of OCT2-mediated ASP+ uptake were obtained from previous literature. A moderate correlation between the inhibition of OCT2-mediated MPP+, ASP+, and metformin uptake was observed (pairwise rs between 0.27 and 0.48, all P < 0.05). Of note, the correlation in the inhibition profile between structurally similar substrates such as MPP+ and ASP+ (Tanimoto similarity T = 0.28) was even lower (rs = 0.27) than the correlation between structurally distinct substrates, such as ASP+ and metformin (T = 0.01; rs = 0.48) or MPP+ and metformin (T = 0.01; rs = 0.40). We identified selective as well as universal OCT2 inhibitors, which inhibited transport by more than 50% of one substrate only or of all substrates, respectively. Our data suggest that the predictive value for drug-drug interactions using experimental substrates rather than the specific victim drug is limited. The importance of the organic cation transporter OCT2 in the renal excretion of cationic drugs raises the possibility of drug-drug interactions (DDIs) in which an inhibitor (perpetrator) drug decreases OCT2-dependent renal clearance of a victim (substrate) drug. In fact, there are clinically significant interactions for drugs that are known substrates of OCT2 such as metformin. To identify drugs as inhibitors for OCT2, individual drugs or entire drug libraries have been investigated in vitro by using experimental probe substrates such as 1-methyl-4-phenylpyridinium (MPP + ) or 4–4-dimethylaminostyryl-N-methylpyridinium (ASP + ). It has been questioned whether the inhibition data obtained with an experimental probe substrate such as MPP + or ASP + might be used to predict the inhibition against other, clinical relevant substrates such as metformin. Here we compared the OCT2 inhibition profile data for the substrates metformin, MPP + and ASP + . We used human embryonic kidney (HEK 293) cells stably overexpressing human OCT2 as the test system to screen 125 frequently prescribed drugs as inhibitors of OCT2-mediated metformin and MPP + uptake. Data on inhibition of OCT2-mediated ASP + uptake were obtained from previous literature. A moderate correlation between the inhibition of OCT2-mediated MPP + , ASP + , and metformin uptake was observed (pairwise r s between 0.27 and 0.48, all P < 0.05). Of note, the correlation in the inhibition profile between structurally similar substrates such as MPP + and ASP + (Tanimoto similarity T = 0.28) was even lower ( r s = 0.27) than the correlation between structurally distinct substrates, such as ASP + and metformin ( T = 0.01; r s = 0.48) or MPP + and metformin ( T = 0.01; r s = 0.40). We identified selective as well as universal OCT2 inhibitors, which inhibited transport by more than 50% of one substrate only or of all substrates, respectively. Our data suggest that the predictive value for drug-drug interactions using experimental substrates rather than the specific victim drug is limited. The importance of the organic cation transporter OCT2 in the renal excretion of cationic drugs raises the possibility of drug-drug interactions (DDIs) in which an inhibitor (perpetrator) drug decreases OCT2-dependent renal clearance of a victim (substrate) drug. In fact, there are clinically significant interactions for drugs that are known substrates of OCT2 such as metformin. To identify drugs as inhibitors for OCT2, individual drugs or entire drug libraries have been investigated in vitro by using experimental probe substrates such as 1-methyl-4-phenylpyridinium (MPP+) or 4-4-dimethylaminostyryl-N-methylpyridinium (ASP+). It has been questioned whether the inhibition data obtained with an experimental probe substrate such as MPP+ or ASP+ might be used to predict the inhibition against other, clinical relevant substrates such as metformin. Here we compared the OCT2 inhibition profile data for the substrates metformin, MPP+ and ASP+. We used human embryonic kidney (HEK 293) cells stably overexpressing human OCT2 as the test system to screen 125 frequently prescribed drugs as inhibitors of OCT2-mediated metformin and MPP+ uptake. Data on inhibition of OCT2-mediated ASP+ uptake were obtained from previous literature. A moderate correlation between the inhibition of OCT2-mediated MPP+, ASP+, and metformin uptake was observed (pairwise rs between 0.27 and 0.48, all P < 0.05). Of note, the correlation in the inhibition profile between structurally similar substrates such as MPP+ and ASP+ (Tanimoto similarity T = 0.28) was even lower (rs = 0.27) than the correlation between structurally distinct substrates, such as ASP+ and metformin (T = 0.01; rs = 0.48) or MPP+ and metformin (T = 0.01; rs = 0.40). We identified selective as well as universal OCT2 inhibitors, which inhibited transport by more than 50% of one substrate only or of all substrates, respectively. Our data suggest that the predictive value for drug-drug interactions using experimental substrates rather than the specific victim drug is limited.The importance of the organic cation transporter OCT2 in the renal excretion of cationic drugs raises the possibility of drug-drug interactions (DDIs) in which an inhibitor (perpetrator) drug decreases OCT2-dependent renal clearance of a victim (substrate) drug. In fact, there are clinically significant interactions for drugs that are known substrates of OCT2 such as metformin. To identify drugs as inhibitors for OCT2, individual drugs or entire drug libraries have been investigated in vitro by using experimental probe substrates such as 1-methyl-4-phenylpyridinium (MPP+) or 4-4-dimethylaminostyryl-N-methylpyridinium (ASP+). It has been questioned whether the inhibition data obtained with an experimental probe substrate such as MPP+ or ASP+ might be used to predict the inhibition against other, clinical relevant substrates such as metformin. Here we compared the OCT2 inhibition profile data for the substrates metformin, MPP+ and ASP+. We used human embryonic kidney (HEK 293) cells stably overexpressing human OCT2 as the test system to screen 125 frequently prescribed drugs as inhibitors of OCT2-mediated metformin and MPP+ uptake. Data on inhibition of OCT2-mediated ASP+ uptake were obtained from previous literature. A moderate correlation between the inhibition of OCT2-mediated MPP+, ASP+, and metformin uptake was observed (pairwise rs between 0.27 and 0.48, all P < 0.05). Of note, the correlation in the inhibition profile between structurally similar substrates such as MPP+ and ASP+ (Tanimoto similarity T = 0.28) was even lower (rs = 0.27) than the correlation between structurally distinct substrates, such as ASP+ and metformin (T = 0.01; rs = 0.48) or MPP+ and metformin (T = 0.01; rs = 0.40). We identified selective as well as universal OCT2 inhibitors, which inhibited transport by more than 50% of one substrate only or of all substrates, respectively. Our data suggest that the predictive value for drug-drug interactions using experimental substrates rather than the specific victim drug is limited. |
| Audience | Academic |
| Author | Fromm, Martin F. Hacker, Kristina Maas, Renke Kornhuber, Johannes Zolk, Oliver |
| AuthorAffiliation | 1 Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany 3 Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, Ulm, Germany Hungarian Academy of Sciences, HUNGARY 2 Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany |
| AuthorAffiliation_xml | – name: 1 Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany – name: 2 Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany – name: 3 Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, Ulm, Germany – name: Hungarian Academy of Sciences, HUNGARY |
| Author_xml | – sequence: 1 givenname: Kristina surname: Hacker fullname: Hacker, Kristina – sequence: 2 givenname: Renke surname: Maas fullname: Maas, Renke – sequence: 3 givenname: Johannes surname: Kornhuber fullname: Kornhuber, Johannes – sequence: 4 givenname: Martin F. surname: Fromm fullname: Fromm, Martin F. – sequence: 5 givenname: Oliver surname: Zolk fullname: Zolk, Oliver |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26327616$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | COPYRIGHT 2015 Public Library of Science 2015 Hacker et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2015 Hacker et al 2015 Hacker et al |
| Copyright_xml | – notice: COPYRIGHT 2015 Public Library of Science – notice: 2015 Hacker et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. – notice: 2015 Hacker et al 2015 Hacker et al |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Feature-1 content type line 23 Competing Interests: M.F.F. received personal compensation for expert testimony from Boehringer Ingelheim and payments for lectures from Bayer-Schering Pharma, Boehringer Ingelheim AG, Janssen-Cilag and Sanofi-Aventis Deutschland GmbH. His institution received compensation for commissioned research of his group from Merck KGaA and from Sanofi-Aventis Deutschland GmbH and for supply for in vitro studies from Gilead. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials. The remaining authors (K.H., R.M., J.K., O.Z.) declare no conflicts of interest. Conceived and designed the experiments: KH RM JK MFF OZ. Performed the experiments: KH OZ. Analyzed the data: KH OZ. Contributed reagents/materials/analysis tools: JK RM MFF OZ. Wrote the paper: KH MFF OZ. |
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| SubjectTerms | 1-Methyl-4-phenylpyridinium - pharmacology Antidiabetics Binding sites Cations Cell Line Comparative analysis Correlation Drug Evaluation, Preclinical Drug Interactions Drugs Excretion Humans In Vitro Techniques Inhibition Inhibitors Kidneys Medical screening Metformin Metformin - pharmacology MPP Oct-2 protein Organic Cation Transport Proteins - antagonists & inhibitors Organic Cation Transport Proteins - metabolism Organic cation transporter Organic Cation Transporter 2 Pharmacology Pyridinium Compounds - pharmacology Renal function Substrate inhibition Substrate Specificity Substrates Toxicology Transporter Verapamil Xenobiotics |
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| Title | Substrate-Dependent Inhibition of the Human Organic Cation Transporter OCT2: A Comparison of Metformin with Experimental Substrates |
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