Metabolism of ticlopidine in rats: identification of the main biliary metabolite as a glutathione conjugate of ticlopidine S-oxide.
We have identified several novel metabolites of ticlopidine, a well known antiplatelet agent and have revealed its metabolic route in rats. The main biliary metabolite of ticlopidine was characterized as a glutathione (GSH) conjugate of ticlopidine S-oxide, in which conjugation had occurred at carbon 7a in the thienopyridine moiety. Quantitative analysis revealed that 29% of the dose was subjected to the formation of reactive intermediates followed by conjugation with GSH after oral administration of ticlopidine (22 mg/kg) to rats. In vitro incubation of ticlopidine with rat liver 9000 g supernatant fraction (S9) fractions led to the formation of multiple metabolites, including 2-oxo-ticlopidine, the precursor for the pharmacologically active ticlopidine metabolite, [1-(2-chlorobenzyl)-4-mercaptopiperidin-(3Z)-ylidene] acetic acid. A novel thiophene ring-opened metabolite with a thioketone group and a carboxylic acid moiety has also been detected after incubation of 2-oxo-ticlopidine with rat liver microsomes or upon incubation of ticlopidine with rat liver S9 fractions.
Shimizu
Shinji
S
Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Hiromachi, Shinagawa-ku, Tokyo, Japan. shimizu.shinji.d3@daiichisankyo.co.jp
Atsumi
Ryo
R
Nakazawa
Tsunenori
T
Fujimaki
Yuko
Y
Sudo
Kenichi
K
Okazaki
Osamu
O
D000818:Animals; D001646:Bile / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics* / Q000652:urine; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D010087:Oxides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013056:Spectrophotometry, Ultraviolet; D013347:Subcellular Fractions / Q000378:metabolism; D013988:Ticlopidine / Q000493:pharmacokinetics* / Q000652:urine
D005343:Fibrinolytic Agents; D010087:Oxides; D005978:Glutathione; D013988:Ticlopidine