Metabolism of pravastatin sodium in isolated rat hepatocytes. I. Glutathione conjugate formation reaction.
1. The metabolic fate of pravastatin sodium (sodium (+)-(3R,5R)-3,5-dihydroxy-7-((1'S,2'S,6'S,8'S,8'aR)-6'-hydroxy-2'methyl- 8'-[(S)-2"-methylbutyryloxy]-1',2',6',7',8', 8'a-hexahydro-1'-naphthyl) heptanoate) was studied in isolated rat hepatocytes. 2. Two polar metabolites were isolated and identified as a glutathione conjugate and a dihydrodiol. 3. Both metabolites were formed via an epoxide which has been identified as the 4'a beta,5' beta-epoxide on the decalin moiety. 4. Formation of the glutathione conjugate was enzymic, while the dihydrodiol was formed by non-enzymic hydrolysis of the epoxide accompanied by the intramolecular migration of the double bond.
Muramatsu
S
S
Analytical and Metabolic Research Laboratories, Sankyo Co. Ltd., Tokyo, Japan.
Miyaguchi
K
K
Iwabuchi
H
H
Matsushita
Y
Y
Nakamura
T
T
Kinoshita
T
T
Tanaka
M
M
Takahagi
H
H
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004790:Enzyme Induction; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D017035:Pravastatin / Q000031:analogs & derivatives / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D065607:Cytochrome P-450 Enzyme Inhibitors; C077184:pravastatin dihydrodiol; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; D017035:Pravastatin