Enzymatic hydrolysis of indometacin farnesil, a prodrug of indomethacin, by carboxylesterase in cultured synovial cells.
The hydrolysis of indometacin farnesil (IMF) in the synovial cells of rat and human and the subcellular fractions of rat liver were investigated in relation to the inhibition of prostaglandin E2 (PGE2) production in the synovial cells. The inhibition of PGE2 production in cultured human synovial cells by anti-inflammatory drugs was potent in the order of IND, IMF and acetyl salicylic acid. However, when the cells were pretreated with IMF, the inhibitory activity of IMF was retained even after the compound was washed out from the medium. No duration of the inhibition was seen in the pretreatment of the cells with IND or acetyl salicylic acid. These results suggest that IMF incorporated into the synovial cells was hydrolyzed gradually to IND. In fact, IMF was taken up by rat synovial cells in culture and considerable amount of IND, which increased with culture period, was found out in the cells. Furthermore, the IMF hydrolase activity was found in microsomal and lysosomal fractions of rat liver, and the hydrolase was identified as carboxylesterase by using bis-(p-nitrophenyl) phosphate, a specific inhibitor of carboxylesterase.
Mishima
M
M
Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan.
Kobayashi
S
S
Hashida
R
R
Yuzuriha
T
T
Sato
T
T
Satoh
T
T
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002478:Cells, Cultured; D015232:Dinoprostone / Q000096:biosynthesis; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007213:Indomethacin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D011355:Prodrugs / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism
D011355:Prodrugs; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase; D015232:Dinoprostone; C060022:indomethacin farnesil; D007213:Indomethacin