Enantioselective metabolism during continuous administration of S-(-)- and R-(+)-nicotine isomers to guinea-pigs.
The S-(-)- and R-(+)-nicotine isomers were administered subcutaneously via Alzet osmotic pumps to male Hartley guinea-pigs (n = 5 with each isomer) over a 23-day period. Estimated dosage rate throughout the experiment was 0.6 mg-1. Urine samples were collected over this time and the levels of urinary oxidative and N-methylated nicotine metabolites were measured by cation-exchange HPLC analysis. S-(-)-Nicotine formed only oxidative metabolites, whereas the R-(+)-isomer formed both oxidative and N-methylated metabolites. 3'-Hydroxycotinine and nicotine-1'-oxide were major metabolites of both enantiomers; cotinine and nornicotine were only minor metabolites. The major N-methylated metabolite of R-(+)-nicotine was N-methylnicotinium ion; N-methylcotininium ion and N-methylnornicotinium ion were also identified as metabolites of this nicotine isomer. Total N-methylated quaternary ammonium metabolites accounted for 15 to 20% of the administered dose of R-(+)-nicotine. An interesting enantioselective reduction in the percent of oxidative urinary metabolites formed S-(-)-nicotine was observed over 23 days. This may indicate the enantioselective induction of an uncharacterized metabolic pathway for this nicotine isomer.
Nwosu
C G
CG
College of Pharmacy, Division of Medicinal Chemistry and Pharmacognosy, University of Kentucky, Lexington 40536-0083.
Godin
C S
CS
Houdi
A A
AA
Damani
L A
LA
Crooks
P A
PA
D000818:Animals; D001711:Biotransformation; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D003367:Cotinine / Q000031:analogs & derivatives / Q000032:analysis / Q000302:isolation & purification / Q000378:metabolism; D006168:Guinea Pigs; D008297:Male; D009538:Nicotine / Q000378:metabolism*; D013237:Stereoisomerism; D013997:Time Factors
C001381:hydroxycotinine; D009538:Nicotine; D003367:Cotinine