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Rapid CommunicationShort Communication

β-Oxidation of Simvastatin in Mouse Liver Preparations

Thomayant Prueksaritanont, Bennett Ma, Xiaojun Fang, Raju Subramanian, Jian Yu and Jiunn H. Lin
Drug Metabolism and Disposition October 2001, 29 (10) 1251-1255;
Thomayant Prueksaritanont
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Bennett Ma
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Xiaojun Fang
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Raju Subramanian
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Jian Yu
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Jiunn H. Lin
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Abstract

All current 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors [simvastatin (SV), lovastatin (LV), atorvastatin, pravastatin, fluvastatin, and cerivastatin] are believed to undergo an atypical β-oxidation of the dihydroxy heptanoic or heptanoic acid side chain. Metabolites, which are shortened by two- and/or four-carbon units consistent with β-oxidation products, have been reported exclusively in rodents following LV and SV administration and across species (rodents, dogs, and humans) following the other statins. In this study, in vitro formation of a β-oxidation product of simvastatin hydroxy acid (SVA) and its intermediates in mouse livers is described. Incubation of SVA with mouse liver preparations fortified with CoASH and ATP led to formation of SV and two major products (P1 and P2). Based on mass spectrometry (MS), tandem mass spectrometry, and/or NMR spectral characteristics, P1 was an α,β-unsaturated metabolite, formed by dehydration of thed,d-dihydroxy heptanoic acid side chain, whereas P2 was probably the l,d-dihydroxy acid isomer of SVA, formed by stereospecific hydration of P1. When NAD+ was also included in the incubation mixture, there were two additional metabolites with the MS and/or NMR characteristics consistent with a two-carbon shortened product (P3) and its dehydrated derivative (P4). In a complete incubation system with all cofactors (ATP, CoASH, NAD+, and NADPH) present, there was an additional product with MS spectra and liquid chromatography retention time identical to the β-oxidized, unsubstituted pentanoic acid metabolite (P5) detected in rats and mice following simvastatin administration. The involvement of CoASH and NAD+ and the presence of the four metabolic intermediates suggest that SVA (and presumably the other statins) is a substrate for the β-oxidation enzyme complex in mice. Additionally, the present finding of CoASH-dependent formation of SV substantiates a mechanism proposed previously for the in vivo lactonization of statin hydroxy acids.

Footnotes

  • Abbreviations used are::
    SV
    simvastatin
    LV
    lovastatin
    SVA
    hydroxy acid form of simvastatin
    LVA
    hydroxy acid form of lovastatin
    HPLC
    high-pressure liquid chromatography
    ACN
    acetonitrile
    LC
    liquid chromatography
    MS
    mass spectrometry
    MS/MS
    tandem mass spectrometry
    • Received March 5, 2001.
    • Accepted June 14, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (10)
Drug Metabolism and Disposition
Vol. 29, Issue 10
1 Oct 2001
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Rapid CommunicationShort Communication

β-Oxidation of Simvastatin in Mouse Liver Preparations

Thomayant Prueksaritanont, Bennett Ma, Xiaojun Fang, Raju Subramanian, Jian Yu and Jiunn H. Lin
Drug Metabolism and Disposition October 1, 2001, 29 (10) 1251-1255;

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Rapid CommunicationShort Communication

β-Oxidation of Simvastatin in Mouse Liver Preparations

Thomayant Prueksaritanont, Bennett Ma, Xiaojun Fang, Raju Subramanian, Jian Yu and Jiunn H. Lin
Drug Metabolism and Disposition October 1, 2001, 29 (10) 1251-1255;
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