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In Vitro Drug-Drug Interaction Potential of Sulfoxide and/or Sulfone Metabolites of Albendazole, Triclabendazole, Aldicarb, Methiocarb, Montelukast and Ziprasidone
BACKGROUND: The use of polypharmacy in the present day clinical therapy has made the identification of clinical drug-drug interaction risk an important aspect of drug development process. Although many drugs can be metabolized to sulfoxide and/or sulfone metabolites, seldom is known on the CYP in-hi...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Bentham Science Publishers
2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416464/ https://www.ncbi.nlm.nih.gov/pubmed/30117405 http://dx.doi.org/10.2174/1872312812666180816164626 |
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author | Giri, Poonam Gupta, Lakshmikant Naidu, Sneha Joshi, Vipul Patel, Nirmal Giri, Shyamkumar Srinivas, Nuggehally R. |
author_facet | Giri, Poonam Gupta, Lakshmikant Naidu, Sneha Joshi, Vipul Patel, Nirmal Giri, Shyamkumar Srinivas, Nuggehally R. |
author_sort | Giri, Poonam |
collection | PubMed |
description | BACKGROUND: The use of polypharmacy in the present day clinical therapy has made the identification of clinical drug-drug interaction risk an important aspect of drug development process. Although many drugs can be metabolized to sulfoxide and/or sulfone metabolites, seldom is known on the CYP in-hibition potential and/or the metabolic fate for such metabolites. OBJECTIVE: The key objectives were: a) to evaluate the in vitro CYP inhibition potential of selected parent drugs with sulfoxide/sulfone metabolites; b) to assess the in vitro metabolic fate of the same panel of par-ent drugs and metabolites. METHODS: In vitro drug-drug interaction potential of test compounds was investigated in two stages; 1) assessment of CYP450 inhibition potential of test compounds using human liver microsomes (HLM); and 2) assessment of test compounds as substrate of Phase I enzymes; including CYP450, FMO, AO and MAO using HLM, recombinant human CYP enzymes (rhCYP), Human Liver Cytosol (HLC) and Human Liver Mitochondrial (HLMit). All samples were analysed by LC-MS-MS method. RESULTS: CYP1A2 was inhibited by methiocarb, triclabendazole, triclabendazole sulfoxide, and ziprasi-done sulfone with IC50 of 0.71 µM, 1.07 µM, 4.19 µM, and 17.14 µM, respectively. CYP2C8 was in-hibited by montelukast, montelukast sulfoxide, montelukast sulfone, tribendazole, triclabendazole sulfox-ide, and triclabendazole sulfone with IC50 of 0.08 µM, 0.05 µM, 0.02 µM, 3.31 µM, 8.95 µM, and 1.05 µM, respectively. CYP2C9 was inhibited by triclabendazole, triclabendazole sulfoxide, triclabendazole sulfone, montelukast, montelukast sulfoxide and montelukast sulfone with IC50 of 1.17 µM, 1.95 µM, 0.69 µM, 1.34 µM, 3.61 µM and 2.15 µM, respectively. CYP2C19 was inhibited by triclabendazole and triclabendazole sulfoxide with IC50 of 0.25 and 0.22, respectively. CYP3A4 was inhibited by monte-lukast sulfoxide and triclabendazole with IC50 of 9.33 and 15.11, respectively. Amongst the studied sul-foxide/sulfone substrates, the propensity of involvement of CY2C9 and CYP3A4 enzyme was high (ap-proximately 56% of total) in the metabolic fate experiments. CONCLUSION: Based on the findings, a proper risk assessment strategy needs to be factored (i.e., perpetra-tor and/or victim drug) to overcome any imminent risk of potential clinical drug-drug interaction when sulfoxide/sulfone metabolite(s) generating drugs are coadministered in therapy. |
format | Online Article Text |
id | pubmed-6416464 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Bentham Science Publishers |
record_format | MEDLINE/PubMed |
spelling | pubmed-64164642019-04-10 In Vitro Drug-Drug Interaction Potential of Sulfoxide and/or Sulfone
Metabolites of Albendazole, Triclabendazole, Aldicarb, Methiocarb, Montelukast and Ziprasidone Giri, Poonam Gupta, Lakshmikant Naidu, Sneha Joshi, Vipul Patel, Nirmal Giri, Shyamkumar Srinivas, Nuggehally R. Drug Metab Lett Article BACKGROUND: The use of polypharmacy in the present day clinical therapy has made the identification of clinical drug-drug interaction risk an important aspect of drug development process. Although many drugs can be metabolized to sulfoxide and/or sulfone metabolites, seldom is known on the CYP in-hibition potential and/or the metabolic fate for such metabolites. OBJECTIVE: The key objectives were: a) to evaluate the in vitro CYP inhibition potential of selected parent drugs with sulfoxide/sulfone metabolites; b) to assess the in vitro metabolic fate of the same panel of par-ent drugs and metabolites. METHODS: In vitro drug-drug interaction potential of test compounds was investigated in two stages; 1) assessment of CYP450 inhibition potential of test compounds using human liver microsomes (HLM); and 2) assessment of test compounds as substrate of Phase I enzymes; including CYP450, FMO, AO and MAO using HLM, recombinant human CYP enzymes (rhCYP), Human Liver Cytosol (HLC) and Human Liver Mitochondrial (HLMit). All samples were analysed by LC-MS-MS method. RESULTS: CYP1A2 was inhibited by methiocarb, triclabendazole, triclabendazole sulfoxide, and ziprasi-done sulfone with IC50 of 0.71 µM, 1.07 µM, 4.19 µM, and 17.14 µM, respectively. CYP2C8 was in-hibited by montelukast, montelukast sulfoxide, montelukast sulfone, tribendazole, triclabendazole sulfox-ide, and triclabendazole sulfone with IC50 of 0.08 µM, 0.05 µM, 0.02 µM, 3.31 µM, 8.95 µM, and 1.05 µM, respectively. CYP2C9 was inhibited by triclabendazole, triclabendazole sulfoxide, triclabendazole sulfone, montelukast, montelukast sulfoxide and montelukast sulfone with IC50 of 1.17 µM, 1.95 µM, 0.69 µM, 1.34 µM, 3.61 µM and 2.15 µM, respectively. CYP2C19 was inhibited by triclabendazole and triclabendazole sulfoxide with IC50 of 0.25 and 0.22, respectively. CYP3A4 was inhibited by monte-lukast sulfoxide and triclabendazole with IC50 of 9.33 and 15.11, respectively. Amongst the studied sul-foxide/sulfone substrates, the propensity of involvement of CY2C9 and CYP3A4 enzyme was high (ap-proximately 56% of total) in the metabolic fate experiments. CONCLUSION: Based on the findings, a proper risk assessment strategy needs to be factored (i.e., perpetra-tor and/or victim drug) to overcome any imminent risk of potential clinical drug-drug interaction when sulfoxide/sulfone metabolite(s) generating drugs are coadministered in therapy. Bentham Science Publishers 2018-12 2018-12 /pmc/articles/PMC6416464/ /pubmed/30117405 http://dx.doi.org/10.2174/1872312812666180816164626 Text en © 2018 Bentham Science Publishers https://creativecommons.org/licenses/by-nc/4.0/legalcode This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited. |
spellingShingle | Article Giri, Poonam Gupta, Lakshmikant Naidu, Sneha Joshi, Vipul Patel, Nirmal Giri, Shyamkumar Srinivas, Nuggehally R. In Vitro Drug-Drug Interaction Potential of Sulfoxide and/or Sulfone Metabolites of Albendazole, Triclabendazole, Aldicarb, Methiocarb, Montelukast and Ziprasidone |
title |
In Vitro Drug-Drug Interaction Potential of Sulfoxide and/or Sulfone
Metabolites of Albendazole, Triclabendazole, Aldicarb, Methiocarb, Montelukast and Ziprasidone |
title_full |
In Vitro Drug-Drug Interaction Potential of Sulfoxide and/or Sulfone
Metabolites of Albendazole, Triclabendazole, Aldicarb, Methiocarb, Montelukast and Ziprasidone |
title_fullStr |
In Vitro Drug-Drug Interaction Potential of Sulfoxide and/or Sulfone
Metabolites of Albendazole, Triclabendazole, Aldicarb, Methiocarb, Montelukast and Ziprasidone |
title_full_unstemmed |
In Vitro Drug-Drug Interaction Potential of Sulfoxide and/or Sulfone
Metabolites of Albendazole, Triclabendazole, Aldicarb, Methiocarb, Montelukast and Ziprasidone |
title_short |
In Vitro Drug-Drug Interaction Potential of Sulfoxide and/or Sulfone
Metabolites of Albendazole, Triclabendazole, Aldicarb, Methiocarb, Montelukast and Ziprasidone |
title_sort | in vitro drug-drug interaction potential of sulfoxide and/or sulfone
metabolites of albendazole, triclabendazole, aldicarb, methiocarb, montelukast and ziprasidone |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416464/ https://www.ncbi.nlm.nih.gov/pubmed/30117405 http://dx.doi.org/10.2174/1872312812666180816164626 |
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