Metabolic fate of 2,2-dimethylbutyryl moiety of simvastatin in rats: Identification of metabolites by gas chromatography/ mass spectrometry
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Metabolic pathways of simvastatin (MK-733), a lactone prodrug of an inhibitor of HMG-CoA reductase, were elucidated in male rats, using the [14C]-labelled compound. Evidence has been obtained for hydrolysis of simvastatin and its metabolites at their 2,2-dimethylbutyryl moieties. Metabolites identified in plasma were 2,2-dimethylbutyric acid (DMB), 2,2-dimemyl-3-hydroxybutyric acid (DMHB) and an open chain hydroxy acid of simvastatin: metabolites identified in urine were DMHB, a glucuronide and the glycine conjugate of DMB. They were characterized by gas chromatography/electron impact and chemical ionization mass spectrometry as phenacyl or pertrimethylsilylated derivatives. The structures of the metabolites and the aglycone of the glucuronide were confirmed as phenacyl esters by comparison of their chromatographic data and mass spectra with those of the phenacyl derivatives of authentic compounds.
Keywords[14C]-Simvastatin rat metabolite 2,2-climethylbutyric acid gas chromatography/mass spectrometry
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- 6.Alberts A.W., Chen J., Huff J., Hunt V., Kuron G. (1986): Comparative studies on the hydroxymethyl-glutaryl coenzyme A reductase inhibitors mevinolin, MK-733 and CS-514. Proc. IXth Int Symp. Drugs Affect Lipid Metab., (Florence), 8.Google Scholar
- 19.Duggan D.E. (1988): The physiological disposition of lovastatin. Proc. 8th Int. Symp. Atherosclerosis (Rome), 1067.Google Scholar
- 20.Vyas K.P. (1988): Metabolism of lovastatin and simvastatin by rat and mouse liver microsomes. Proc. 8th Int. Symp. Atherosclerosis (Rome), 1068.Google Scholar
- 22.Ohtawa M., Uchiyama N., Saito Y., et al. (1989): Phase I study of MK-733, an inhibitor of HMG-CoA reductase II: pharmacokinetics of MK-733 in healthy subjects after single and multiple oral administration. J. Clin. Ther. Med., 5, 1123–1140.Google Scholar