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First published on February 15, 2007; DOI: 10.1124/dmd.106.013334

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Received for publication November 1, 2006.
Revised February 9, 2007.
Accepted for publication February 12, 2007.

Studies on the Metabolism of Tolmetin to the Chemically Reactive Acyl-Coenzyme A Thioester Intermediate in Rats

Jorgen Olsen 1*, Chunze Li 2, Christian Skonberg 3, Inga Bjornsdottir 1, Ulrik Sidenius 3, Leslie Benet 4, Steen Honore Hansen 3

1 Novo Nordisk A/S 2 Merck Research Labs 3 The Danish University of Pharmaceutical Sciences 4 University of California, San Francisco

* Address correspondence to: E-mail: jqgo{at}novonordisk.com

Abstract

Carboxylic acids may be metabolized to acyl glucuronides and acyl-coenzyme A thioesters (acyl-CoAs), which are reactive metabolites capable of reacting with proteins in vivo. In this study, the metabolic activation of tolmetin (Tol) to reactive metabolites and the subsequent formation of Tol-protein adducts in the liver were studied in rats. Two hours after dose administration (100 mg/kg, i.p.), tolmetin acyl-CoA (Tol-CoA) was identified by LC-MS/MS in liver homogenates. Similarly, the acyl-CoA dependent metabolites tolmetin-taurine conjugate (Tol-Tau) and tolmetin-acyl carnitine ester (Tol-Car) were identified in rat livers. In a rat bile study (100 mg/kg, i.p.), the S-acyl glutathione thioester conjugate was identified, providing further evidence of the formation of reactive metabolites such as Tol-CoA or Tol-acyl glucuronide (Tol-O-G), capable of acylating nucleophilic functional groups. Three rats were treated with clofibric acid (150 mg/kg/day, i.p. for 7 days) prior to dose administration of Tol. This resulted in an increase in covalent binding to liver proteins from 0.9 nmol/g liver in control rats to 4.2 nmol/g liver in clofibric acid treated rats. Similarly, levels of Tol-CoA increased from 0.6 nmol/g to 4.4 nmol/g liver following pre-treatment with clofibric acid, whereas the formation of Tol-O-G and Tol-Tau formation was unaffected by clofibric acid treatment. However, Tol-Car levels increased from 0.08 to 0.64 nmol/g following clofibric acid treatment. Collectively, these results confirm that Tol-CoA is formed in vivo in the rat and that this metabolite can have important consequences in terms of covalent binding to liver proteins.


Key words: analytical chemistry, bioactivation, covalent drug binding, glutathione conjugates, reactive intermediate, reactive metabolites


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Differential Effects of Fibrates on the Metabolic Activation of 2-Phenylpropionic Acid in Rats
Drug Metab. Dispos., April 1, 2008; 36(4): 682 - 687.
[Abstract] [Full Text] [PDF]


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