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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...

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Autores principales: Giri, Poonam, Gupta, Lakshmikant, Naidu, Sneha, Joshi, Vipul, Patel, Nirmal, Giri, Shyamkumar, Srinivas, Nuggehally R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Bentham Science Publishers 2018
Materias:
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.
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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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