Document Detail


Mechanism-based inactivation of cytochrome P450 2C9 by tienilic acid and (+/-)-suprofen: a comparison of kinetics and probe substrate selection.
MedLine Citation:
PMID:  18838506     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
J Matthew Hutzler; Larissa M Balogh; Michael Zientek; Vikas Kumar; Timothy S Tracy
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural     Date:  2008-10-06
Journal Detail:
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:
Created Date:  2008-12-24     Completed Date:  2009-03-02     Revised Date:  2010-09-21    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  59-65     Citation Subset:  IM    
Affiliation:
Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, St. Louis Laboratories, St. Louis, Missouri, USA. j.matt.hutzler@pfizer.com
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MeSH Terms
Descriptor/Qualifier:
Anti-Inflammatory Agents, Non-Steroidal / 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:
GM069753/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
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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