Metabolic fate of 2,2-dimethylbutyryl moiety of simvastatin in rats: Identification of metabolites by gas chromatography/ mass spectrometry

Abstract

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-dimethyl-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.

Simvastatin: In Vitro Metabolic Profiling of a Potent Competitive HMG-CoA Reductase Inhibitor

“…The identified possible SV metabolites in the rat in vitro experiment were in accordance with previously reported SV metabolites [29][30][31][32][33]. In addition, we detected some possible SVA metabolites in this experiment (Section 3.3.1), which, to the best of our knowledge, have beeen reported only once in a paper, where SVA was used as a substrate instead of SV to identify the responsiblility of CYP450 isoforms for the metabolism of SVA in human liver microsomes (HLMs) [48].…”

“…To date, thirteen metabolites of SV have been identified, which are depicted in Figure 2. Five metabolites 5-9 of SV were identified in rat plasma and urine using gas chromatography-mass spectrometry (GC-MS) [29]. In addition to that work, using HPLC-UV, six other metabolites 10-15 including metabolite 5 were detected in rat hepatic microsomes [30], and using NMR and mass spectroscopy [31] the same were detected in rat liver microsomes (RLMs).…”

“…In order to maximize its excellent cholesterol-lowering effect and minimize its serious side effects, an in-depth study of its metabolism becomes indispensable to understand the mechanisms underlying its pharmacological effects and its potential side effects. Metabolic profiling of SV has been reported in a number of articles using different analytical methods [29][30][31][32][33]. To date, thirteen metabolites of SV have been identified, which are depicted in Figure 2.…”

“…Metabolic profiling of SV has been reported in a number of articles using different analytical methods [29][30][31][32][33]. To date, thirteen metabolites of SV have been identified, which are depicted in Figure 2.…”

Fragmentation study of simvastatin and lovastatin using electrospray ionization tandem mass spectrometry

“…Simvastatin and lovastatin are two well‐known compounds for lowering plasma cholesterol levels by inhibiting HMG‐CoA reductase 1–4. Many quantitative and qualitative mass spectrometric studies have been reported for simvastatin and lovastatin in biological samples 5–13. For qualitative studies, metabolite identification from animal and clinical studies has been accomplished using mass spectrometry.…”