Structural characterization of in vivo rat glutathione adducts and a hydroxylated metabolite of simvastatin hydroxy acid.
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'beta,6'beta-dihydroxy-4'a(alpha)-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'beta,6'beta-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.
Subramanian
Raju
R
Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. raju_subramanian@merck.com
Fang
Xiaojun
X
Prueksaritanont
Thomayant
T
D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism*; D006900:Hydroxylation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012588:Scintillation Counting; D019821:Simvastatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D013045:Species Specificity; D021241:Spectrometry, Mass, Electrospray Ionization
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C063287:simvastatin acid; D019821:Simvastatin; D005978:Glutathione