Biotransformation of pravastatin sodium (I). Mechanisms of enzymic transformation and epimerization of an allylic hydroxy group of pravastatin sodium.
One of the major metabolites, R-416(3'alpha-OH), of pravastatin sodium(PV, 6'beta-OH), and a minor metabolite, R-418 (6'alpha-OH), were produced in rat liver cytosol in the presence of adenosine 3'-phosphate 5'-phosphosulfate as a cofactor. The reactions were inhibited by the inhibitors for sulfotransferases, and 18OH was introduced to the 3'alpha- and 6'alpha-positions of R-416 and R-418, respectively, by incubation with H2 18O. These results strongly suggested that PV was metabolically activated by sulfation at the 6'beta-hydroxy group by sulfotransferases, followed by nucleophilic attack of hydroxy anions at the 3'alpha- or 6'alpha-position, to give R-416 or R-418, respectively.
Kitazawa
E
E
Analytical and Metabolic Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Tamura
N
N
Iwabuchi
H
H
Uchiyama
M
M
Muramatsu
S
S
Takahagi
H
H
Tanaka
M
M
D000818:Animals; D001711:Biotransformation; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D017035:Pravastatin / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D017035:Pravastatin