AMINE N -METHYLTRANSFERASE STUDIES IN RAT, GUINEA PIG, HAMSTER AND RABBIT WITH SPECIAL EMPHASIS ON NICOTINE N -METHYLATION IN VIVO

Investigation of the biological N -methylation of amines has been conducted in this dissertation. Tryptamine and pyridine N -methylation reactions have been evaluated in vitro using rabbit lung and liver homogenates. The N -methylated derivatives of tryptamine and pyridine have been synthesized and used in the development of analytical systems, based upon high performance liquid chromatography (HPLC). These analytical systems have allowed the unambiguous determination of the identity of the N -methylated derivatives of these amino compounds which are formed in tissue homogenates that have been incubated with S -adenosyl-L- (;Although the levels of oxidative metabolites of each enantiomer of nicotine among the animal species studied were somewhat different, significant species and sex differences also existed in the comparative oxidative metabolism of the nicotine enantiomers. Guinea pig (male Hartley) was the only species studied which was able to N -methylate nicotine.;N -Methylation of nicotine has been studied in vivo in the guinea pig after long term subcutaneous administration of non-radiolabeled nicotine enantiomers. HPLC analyses revealed that 3-hydroxycotinine was the major urinary metabolite of both nicotine enantiomers. Nicotine- N ;This study has shown that N -methylation pathway of metabolites could be an important route in the biotransformation of xenobiotics, particularly those that contain azaheterocyclic groupings. The nicotine studies may well be of use in chosing the appropriate animal model for smoking and nicotine exposure studies as they relate to man. Since it is known that man is capable of N -methylating both nicotine and cotinine, this may suggest that the guinea pig is a comparable metabolic animal model for smoking and nicotine exposure studies. (Abstract shortened with permission of author.);The in vivo metabolism of radiolabeled nicotine enantiomers to oxidative and N -methylated nicotine compounds has been studied. Analyses revealed that significant differences exist in the metabolism of radiolabeled nicotine enantiomers among the different animal species.