Abstract
Simvastatin hydroxy acid (SVA), the pharmacologically active form of simvastatin (SV), is a potent inhibitor of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A reductase and is formed on hydrolysis of the orally administered SV. In this article, we report the structural characterization of two new dihydroxy glutathione adducts and a trihydroxy derivative of SVA, all found in rat bile. Metabolite I is 5′β,6′β-dihydroxy-4′aα-glutathione-SVA, and metabolite II is a pentanoic acid derivative of metabolite I. The two identified GSH conjugates accounted for 16 and 9% in males and 11 and 5% in females of the total radioactivity (metabolites I and II, respectively). Metabolite III is 3′,5′β,6′β-dihydrotriol-SVA and accounts for 2% (male) and 4% (female) of the total dose in rats. Of these three newly identified metabolites, only metabolite III was also observed in dog bile.
Footnotes
- Abbreviations used are::
- SVA
- simvastatin hydroxy acid
- SV
- simvastatin
- HMG
- 3-hydroxy-3-methylglutaryl
- HPLC
- high-performance liquid chromatography
- LC
- liquid chromatography
- MS
- mass spectrometry
- MS/MS
- tandem mass spectrometry
- 1D
- one dimensional
- 2D
- two dimensional
- TOCSY
- total correlation spectroscopy
- HMQC
- heteronuclear multiple quantum coherence
- ROESY
- rotating Overhauser effect spectroscopy
- NOE
- nuclear Overhauser effect
- GSH
- glutathione
- Received October 19, 2001.
- Accepted December 10, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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