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Drug Metabolism and Disposition Fast Forward
First published on October 26, 2005; DOI: 10.1124/dmd.105.006650

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Received for publication August 4, 2005.
Revised October 20, 2005.
Accepted for publication October 21, 2005.

ACYL-COENZYME A FORMATION OF SIMVASTATIN IN MOUSE LIVER PREPARATIONS

Chunze Li 1*, Raju Subramanian 2, Sean Yu 1, Thomayant Prueksaritanont 1

1 Merck Research Laboratories 2 Amgen Inc.

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

Abstract

Formation of an acyl-CoA thioester has been proposed, but not directly demonstrated, to be a key step in mediating both lactonization and atypical {beta}-oxidation of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors. Here, we describe studies to characterize formation of acyl-CoA thioesters in vitro in mouse liver preparations, using the hydroxy acid form of simvastatin (SVA) as a model substrate. With an optimized chromatography method, three new products were detected in addition to the dehydration product (P1) and the lactone form of simvastatin, which have been characterized previously (Prueksaritanont et al., 2001). Based on HPLC analysis, UV spectroscopy, mass spectrometry and NMR spectral characterization, two metabolites were identified as acyl-CoA thioester conjugates of SVA and P1, respectively, whereas the third metabolite (M1) was confirmed to be the L-{beta}-hydroxy isomer of simvastatin. M1 was likely formed by stereospecific hydration, a previously reported reaction, and subsequent lactonization of P1-S-acyl CoA. Among all the mouse liver subcellular fractions, microsomes exhibited the highest capacity to catalyze the CoASH-dependent metabolism of SVA, while such activity was totally absent in cytosol. Together, these results provide direct experimental evidence that SVA (and conceivably other statins as well) is able to form an acyl-CoA thioester, possibly by microsomal long-chain acyl-CoA synthetase(s), leading to formation of two parallel metabolic pathways; one resulting in the two diastereomers of statin lactones (simvastatin and M1), and the other to the {beta}-oxidation pathway of statin hydroxy acids.


Key words: metabolite identification, phase II drug metabolism


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