Metabolic fate of 2,2-dimethylbutyryl moiety of simvastatin in rats: identification of metabolites by gas chromatography/mass spectrometry.
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.
Uchiyama
N
N
Central Research Laboratories, Banyu Pharmaceutical Co. Ltd., Tokyo, Japan.
Kagami
Y
Y
Saito
Y
Y
Abe
S
S
Ohtawa
M
M
Hata
S
S
D000818:Animals; D002087:Butyrates / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D006868:Hydrolysis; D006885:Hydroxybutyrates / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D019821:Simvastatin
D002087:Butyrates; D006885:Hydroxybutyrates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C074678:2,2-dimethyl-3-hydroxybutyric acid; D008148:Lovastatin; D019821:Simvastatin; C074677:2,2-dimethylbutyric acid