Stereoselective glucuronidation and hydroxylation of etodolac by UGT1A9 and CYP2C9 in man.
1. In vitro metabolic studies with etodolac were performed. S- and R-etodolac were converted to the acylglucuronide and hydroxylated metabolites by UDP-glucuronosyltransferase (UGT) and cytochrome P450 in microsomes. However, the stereoselectivities of UGT and P450 for the isomers were opposite. S-etodolac was glucuronidated preferentially than R-etodolac by UGT. In contrast, R-etodolac was hydroxylated preferentially than S-etodolac by P450. 2. Of several human P450 enzymes, CYP2C9 had the greatest activity for hydroxylation of R-etodolac. Sulfaphenazole, an inhibitor of CYP2C9, and anti-CYP2C9 antibody inhibited the hydroxylation of R-etodolac in human liver microsomes. CYP2C9 therefore contributes to the stereoselective hydroxylation of R-etodolac. 3. Of several human UGT enzymes, UGT1A9 had the greatest activity for glucuronidation of S-etodolac. Propofol and thyroxine, inhibitors of UGT1A9, inhibited the glucuronidation of S-etodolac in human liver microsomes. Therefore, UGT1A9 is mainly responsible for the stereoselective glucuronidation of S-etodolac. 4. Because S-etodolac was metabolized more rapidly than R-etodolac in human cryopreserved hepatocytes, the stereoselectivities of UGT1A9 for etodolac substantially influenced the overall metabolism of S- and R-etodolac in man.
Tougou
K
K
Discovery Research Laboratories Nippon Shinyaku Co., Ltd 14 Nishinosho-Monguchi-Cho Kisshoin Minami-ku Kyoto 601-8550 Japan.
Gotou
H
H
Ohno
Y
Y
Nakamura
A
A
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D065729:Cytochrome P-450 CYP2C9; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017308:Etodolac / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D005965:Glucuronates / Q000737:chemistry / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015742:Propofol / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013237:Stereoisomerism; D013426:Sulfaphenazole / Q000494:pharmacology; D013974:Thyroxine / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D005965:Glucuronates; D007527:Isoenzymes; D011994:Recombinant Proteins; C412945:etodolac glucuronide; D013426:Sulfaphenazole; D017308:Etodolac; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D014453:Glucuronosyltransferase; D013974:Thyroxine; D015742:Propofol