Cis-flupentixol metabolites in rat plasma and bile. The first proof of glutathione conjugation at the exocyclic double bond.
The plasma and biliary metabolites of cis-flupentixol (cis-FPT) were studied after ip administration to rats. Cis-FPT sulfoxide was found to be the major phase-I metabolite in plasma and bile. Five biliary metabolites were isolated by gradient elution HPLC and characterized by various spectroscopic methods: F1, 1'-S-glutathionyl-10,1'-dihydroFPT sulfoxide; F2, cis-FPT sulfoxide sulfate; F3, 8-O-(or 7-O) glucuronyl-cis-FPT; F4, cis-FPT sulfoxide; and F5, cis-FPT glucuronide. A novel non-enzymatic addition of glutathione (GSH) onto the exocyclic double bond was demonstrated to occur for the first time with not only flupentixol and certain of its metabolites, but also with other psychotropic drugs with a tricyclic nucleus and an exocyclic double bond. Specifically, these nonenzymatic additions of GSH were observed with cis-FPT, trans-FPT, cis-FPT sulfoxide, cis-, trans-dealkylFPT, cis-FPT N-oxide, cis-chlorprothixene, cis-thiothixene, and cyclobenzaprine. Among them, cis-FPT sulfoxide showed the most potent adduct formation activity, and the product was characterized to be identical with the in vivo metabolite F1 of cis-FPT.
Shu
Y Z
YZ
College of Pharmacy, University of Saskatchewan, Saskatoon, Canada.
Hubbard
J W
JW
McKay
G
G
Hawes
E M
EM
Midha
K K
KK
D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D005260:Female; D005475:Flupenthixol / Q000097:blood / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D013058:Mass Spectrometry; D011619:Psychotropic Drugs / Q000378:metabolism; D051381:Rats; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
D011619:Psychotropic Drugs; D005475:Flupenthixol; D005978:Glutathione