![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 27, Issue 3, 365-372, March 1999
Department of Drug Metabolism, Merck Research Laboratories, Rahway,
New Jersey (W.T., R.S., Y.Z., C.R., M.B., D.D., J.P., K.H.L., G.A.D.,
J.R.S., G.Y.K., S-H.L.C., T.A.B.);
Faculty of Pharmaceutical Sciences,
University of British Columbia, Vancouver, British Columbia, Canada
(S.M.B.); and
Department of Drug Metabolism, Merck Research
Laboratories, West Point, Pennsylvania (T.H.R., T.A.B.)
The nonsteroidal anti-inflammatory drug diclofenac causes a rare
but potentially fatal hepatotoxicity that may be associated with the
formation of reactive metabolites. In this study, three glutathione
(GSH) adducts, namely
5-hydroxy-4-(glutathion-S-yl)diclofenac (M1),
4'-hydroxy-3'-(glutathion-S-yl)diclofenac (M2), and
5-hydroxy-6-(glutathion-S-yl)diclofenac (M3), were
identified by liquid chromatography-tandem mass spectrometry analysis
of bile from Sprague-Dawley rats injected i.p. with a single dose of
diclofenac (200 mg/kg). These adducts presumably were formed via
hepatic cytochrome P-450 (CYP)-catalyzed oxidation of diclofenac to
reactive benzoquinone imines that were trapped by GSH conjugation. In
support of this hypothesis, M1, M2, and M3 were generated from
diclofenac in incubations with rat liver microsomes in the presence of
NADPH and GSH. Increases in adduct formation were observed when
incubations were performed with liver microsomes from phenobarbital- or
dexamethasone-treated rats. Adduct formation was inhibited by
polyclonal antibodies against CYP2B, CYP2C, and CYP3A (40-50%
inhibition at 5 mg of IgG/nmol of CYP) but not by an antibody against
CYP1A. Maximal inhibition was obtained when the three inhibitory
antibodies were used in a cocktail fashion (70-80% inhibition at 2.5 mg of each IgG/nmol of CYP). These data suggest that diclofenac
undergoes biotransformation to reactive metabolites in rats and that
CYP isoforms of the 2B, 2C, and 3A subfamilies are involved in this
bioactivation process. With respect to CYP2C isoforms, rat hepatic
CYP2C7 and CYP2C11 were implicated as mediators of the bioactivation
based on immunoinhibition studies using antibodies specific to CYP2C7
and CYP2C11. Screening for GSH adducts also was carried out in human
hepatocyte cultures containing diclofenac, and M1, M2, and M3 again
were detected. It is possible, therefore, that reactive benzoquinone
imines may be formed in vivo in humans and contribute to
diclofenac-mediated hepatic injury.
This article has been cited by other articles:
|
|
 |
|
  E. Sjogren, H. Lennernas, T. B. Andersson, J. Grasjo, and U. Bredberg The Multiple Depletion Curves Method Provides Accurate Estimates of Intrinsic Clearance (CLint), Maximum Velocity of the Metabolic Reaction (Vmax), and Michaelis Constant (Km): Accuracy and Robustness Evaluated through Experimental Data and Monte Carlo Simulations Drug Metab. Dispos., January 1, 2009; 37(1): 47 - 58. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Grillo, J. Ma, Y. Teffera, and D. J. Waldon A Novel Bioactivation Pathway for 2-[2-(2,6-Dichlorophenyl)aminophenyl]ethanoic Acid (Diclofenac) Initiated by Cytochrome P450-Mediated Oxidative Decarboxylation Drug Metab. Dispos., September 1, 2008; 36(9): 1740 - 1744. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Osorio-Lozada, S. Surapaneni, G. L. Skiles, and R. Subramanian Biosynthesis of Drug Metabolites Using Microbes in Hollow Fiber Cartridge Reactors: Case Study of Diclofenac Metabolism by Actinoplanes Species Drug Metab. Dispos., February 1, 2008; 36(2): 234 - 240. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Chen, G. A. Doss, E. C. Tung, W. Liu, Y. S. Tang, M. P. Braun, V. Didolkar, J. R. Strauss, R. W. Wang, R. A. Stearns, et al. EVIDENCE FOR THE BIOACTIVATION OF ZOMEPIRAC AND TOLMETIN BY AN OXIDATIVE PATHWAY: IDENTIFICATION OF GLUTATHIONE ADDUCTS IN VITRO IN HUMAN LIVER MICROSOMES AND IN VIVO IN RATS Drug Metab. Dispos., January 1, 2006; 34(1): 145 - 151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Yan, J. Li, N. Huebert, G. W. Caldwell, Y. Du, and H. Zhong DETECTION OF A NOVEL REACTIVE METABOLITE OF DICLOFENAC: EVIDENCE FOR CYP2C9-MEDIATED BIOACTIVATION VIA ARENE OXIDES Drug Metab. Dispos., June 1, 2005; 33(6): 706 - 713. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Yu, Y. Chen, M. P. Deninno, T. N. O'Connell, and C. E. C. A. Hop IDENTIFICATION OF A NOVEL GLUTATHIONE ADDUCT OF DICLOFENAC, 4'-HYDROXY-2'-GLUTATHION-DESCHLORO-DICLOFENAC, UPON INCUBATION WITH HUMAN LIVER MICROSOMES Drug Metab. Dispos., April 1, 2005; 33(4): 484 - 488. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Grillo, C. G. Knutson, P. E. Sanders, D. J. Waldon, F. Hua, and J. A. Ware STUDIES ON THE CHEMICAL REACTIVITY OF DICLOFENAC ACYL GLUCURONIDE WITH GLUTATHIONE: IDENTIFICATION OF DICLOFENAC-S-ACYL-GLUTATHIONE IN RAT BILE Drug Metab. Dispos., November 1, 2003; 31(11): 1327 - 1336. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. K. Poon, Q. Chen, Y. Teffera, J. S. Ngui, P. R. Griffin, M. P. Braun, G. A. Doss, C. Freeden, R. A. Stearns, D. C. Evans, et al. Bioactivation of Diclofenac via Benzoquinone Imine Intermediates---Identification of Urinary Mercapturic Acid Derivatives in Rats and Humans Drug Metab. Dispos., December 1, 2001; 29(12): 1608 - 1613. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Masubuchi, A. Ose, and T. Horie Mechanism-Based Inactivation of CYP2C11 by Diclofenac Drug Metab. Dispos., September 1, 2001; 29(9): 1190 - 1195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. King, W. Tang, J. Ngui, T. Tephly, and M. Braun Characterization of Rat and Human UDP-Glucuronosyltransferases Responsible for the in Vitro Glucuronidation of Diclofenac Toxicol. Sci., May 1, 2001; 61(1): 49 - 53. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Ngui, W. Tang, R. A. Stearns, M. Shou, R. R. Miller, Y. Zhang, J. H. Lin, and T. A. Baillie Cytochrome P450 3A4-Mediated Interaction of Diclofenac and Quinidine Drug Metab. Dispos., September 1, 2000; 28(9): 1043 - 1050. [Abstract] [Full Text]
|
|
|
|
 |
|
 Y. Masubuchi, S. Yamada, and T. Horie Possible Mechanism of Hepatocyte Injury Induced by Diphenylamine and Its Structurally Related Nonsteroidal Anti-Inflammatory Drugs J. Pharmacol. Exp. Ther., March 1, 2000; 292(3): 982 - 987. [Abstract] [Full Text]
|
|
|
|
|
|
W. Tang, R. A. Stearns, G. Y. Kwei, S. A. Iliff, R. R. Miller, M. A. Egan, N. X. Yu, D. C. Dean, S. Kumar, M. Shou, et al. Interaction of Diclofenac and Quinidine in Monkeys: Stimulation of Diclofenac Metabolism J. Pharmacol. Exp. Ther., December 1, 1999; 291(3): 1068 - 1074. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
