| Mechanism-based inactivation of cytochrome P450 2C9 by tienilic acid and (+/-)-suprofen: a comparison of kinetics and probe substrate selection. | |
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MedLine Citation:
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PMID: 18838506 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In vitro experiments were conducted to compare k(inact), K(I) and inactivation efficiency (k(inact)/K(I)) of cytochrome P450 (P450) 2C9 by tienilic acid and (+/-)-suprofen using (S)-flurbiprofen, diclofenac, and (S)-warfarin as reporter substrates. Although the inactivation of P450 2C9 by tienilic acid when (S)-flurbiprofen and diclofenac were used as substrates was similar (efficiency of approximately 9 ml/min/micromol), the inactivation kinetics were characterized by a sigmoidal profile. (+/-)-Suprofen inactivation of (S)-flurbiprofen and diclofenac hydroxylation was also described by a sigmoidal profile, although inactivation was markedly less efficient (approximately 1 ml/min/micromol). In contrast, inactivation of P450 2C9-mediated (S)-warfarin 7-hydroxylation by tienilic acid and (+/-)-suprofen was best fit to a hyperbolic equation, where inactivation efficiency was moderately higher (10 ml/min/micromol) and approximately 3-fold higher (3 ml/min/micromol), respectively, relative to that of the other probe substrates, which argues for careful consideration of reporter substrate when mechanism-based inactivation of P450 2C9 is assessed in vitro. Further investigations into the increased inactivation seen with tienilic acid relative to that with (+/-)-suprofen revealed that tienilic acid is a higher affinity substrate with a spectral binding affinity constant (K(s)) of 2 microM and an in vitro half-life of 5 min compared with a K(s) of 21 microM and a 50 min in vitro half-life for (+/-)-suprofen. Lastly, a close analog of tienilic acid with the carboxylate functionality replaced by an oxirane ring was devoid of inactivation properties, which suggests that an ionic binding interaction with a positively charged residue in the P450 2C9 active site is critical for recognition and mechanism-based inactivation by these close structural analogs. |
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Authors:
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J Matthew Hutzler; Larissa M Balogh; Michael Zientek; Vikas Kumar; Timothy S Tracy |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural Date: 2008-10-06 |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 37 ISSN: 1521-009X ISO Abbreviation: Drug Metab. Dispos. Publication Date: 2009 Jan |
Date Detail:
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Created Date: 2008-12-24 Completed Date: 2009-03-02 Revised Date: 2010-09-21 |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: United States |
Other Details:
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Languages: eng Pagination: 59-65 Citation Subset: IM |
Affiliation:
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Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, St. Louis Laboratories, St. Louis, Missouri, USA. j.matt.hutzler@pfizer.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Anti-Inflammatory Agents, Non-Steroidal
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pharmacokinetics,
pharmacology* Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors* Chromatography, Liquid Diuretics / pharmacokinetics, pharmacology* Enzyme Inhibitors / pharmacokinetics, pharmacology* Spectrophotometry, Ultraviolet Substrate Specificity Suprofen / pharmacokinetics, pharmacology* Tandem Mass Spectrometry Ticrynafen / pharmacokinetics, pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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GM069753/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Anti-Inflammatory Agents, Non-Steroidal; 0/Diuretics; 0/Enzyme Inhibitors; 40180-04-9/Ticrynafen; 40828-46-4/Suprofen; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/CYP2C9 protein, human |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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