DMD Simcyp

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on June 24, 2004; DOI: 10.1124/dmd.104.000034

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.104.000034v1
32/9/1015    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Karanam, B. V
Right arrow Articles by Vincent, S. H
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Karanam, B. V
Right arrow Articles by Vincent, S. H


Received for publication April 5, 2004.
Revised June 16, 2004.
Accepted for publication June 22, 2004.

In Vitro Metabolism of MK-0767, a PPAR alpha/delta Agonist I. Role of Cytochrome P450, Methyltransferases, Flavin Monooxygenases and Esterases

Bindhu V Karanam 1*, Cornelis E.C.A. Hop 1, David Q Liu 1, Mike Wallace 1, Dennis Dean 1, Hiroya Satoh 2, Masakatsu Komuro 2, Katsuya Awano 2, Stella H Vincent 1

1 Merck Research Laboratories, Rahway, NJ 2 Kyorin Pharmaceutical Co., Japan

* Address correspondence to: E-mail: bindhu_karanam{at}merck.com

Abstract

The metabolism of MK-0767, (±)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[4-trifluoromethyl) phenyl]methy]benzamide, a thiazolidinedione (TZD)-containing PPAR {alpha}/{gamma} agonist, was studied in liver microsomes and hepatocytes from humans, rat, dog and rhesus monkey, to characterize the enzyme(s) involved in its metabolism. The major site of metabolism is the TZD ring, which underwent opening catalyzed by CYP3A4 to give the mercapto derivative, M22. Other metabolites formed in NADPH-fortified liver microsomes included the TZD-5-OH derivative (M24), also catalyzed by CYP3A4, and the O-desmethyl derivative (M28), whose formation was catalyzed by CYP2C9 and CYP2C19. Metabolite profiles from hepatocyte incubations were different from those generated with NADPH-fortified microsomal incubations. In addition to M22, M24 and M28, hepatocytes generated several S-methylated metabolites, including the methyl mercapto (M25), the methyl sulfoxide (M16) and the methyl sulfone (M20) metabolites. Addition of the methyl donor, S-adenosyl methionine (SAM), in addition to NADPH to microsomal incubations, enhanced the turnover and resulted in similar metabolite profiles to those in hepatocyte incubations. Collectively, these results show that methyltransferases played a major role in the metabolism of MK-0767. Using enzyme-specific inhibitors, it was concluded that microsomal methyltransferases (TMT) play a more important role than the cytosolic methyltransferase (TPMT). Baculovirus expressed human FMO3, as well as CYP3A4, oxidized M25 to M16, while further oxidation of M16 to M20 was catalyzed mainly by CYP3A4. Esterases were involved in the formation of the methyl sulfone carboxylic acids, minor metabolites detected in hepatocytes.


Key words: antibodies, cytochrome P450 catalyzed oxidations, flavin-containing monooxygenase, hepatocytes, HPLC, human CYP enzymes, inhibition, methyl transferase, microsomes, monooxygenases


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
C. J. Kochansky, R. K. Rippley, K. X. Yan, H. Song, M. A. Wallace, D. Dean, A. N. Jones, K. Lasseter, J. Schwartz, S. H. Vincent, et al.

Drug Metab. Dispos., September 1, 2006; 34(9): 1457 - 1461.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
B. V. Karanam, C. J. Welch, V. G. Reddy, J. Chilenski, M. Biba, and S. Vincent

Drug Metab. Dispos., October 1, 2004; 32(10): 1061 - 1068.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
V. B. G. Reddy, G. A. Doss, M. Creighton, C. J. Kochansky, S. H. Vincent, R. B. Franklin, and B. V. Karanam

Drug Metab. Dispos., October 1, 2004; 32(10): 1154 - 1161.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
D. Q. Liu, B. V. Karanam, G. A. Doss, R. R. Sidler, S. H. Vincent, and C. E.C.A. Hop

Drug Metab. Dispos., September 1, 2004; 32(9): 1023 - 1031.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2004 by the American Society for Pharmacology and Experimental Therapeutics.