Increased cotinine elimination and cotinine-N-oxide formation by phenobarbital induction in rat and mouse.
The metabolic fate of cotinine, the major metabolite of nicotine, was studied in phenobarbital-induced and non-induced isolated perfused rat lung and liver and in isolated hepatocytes of rats and mice. The non-induced lung tissue showed low cotinine metabolizing capacity while the perfused liver was approximately four times more active. After phenobarbital pretreatment the metabolism of cotinine was increased eight-fold in the intact liver. A substantial increase in cotinine metabolism was also found in isolated hepatocytes from PB-induced rats and in cultured mouse hepatocytes grown in a medium supplemented with PB. This was paralleled by an increased formation of cotinine-N-oxide which could be inhibited by 100 microM metyrapone. In contrast, the pulmonary elimination of cotinine was not affected by PB. A dominant role of primary N-oxidation of nicotine compared to C-oxidation was apparent in non-induced rat liver. After PB treatment the rate of nicotine-N'-oxide formation dropped markedly while the cotinine related pathways were increased causing an inversion of the N- to C-oxidation ratio. In the lung, cotinine formation was the preferred metabolic pathway of nicotine already in non-induced organs. The pattern of nicotine metabolites was not altered by PB induction. In conscious PB-induced rats receiving nicotine orally or intravenously, 3'-hydroxycotinine was found as the main urinary metabolite of nicotine while only a small fraction was excreted as cotinine-N-oxide. This discrepancy between the profile of nicotine metabolites in perfused liver and lung and in the urine in vivo indicates that extrahepatic organs other than the lung may be important sites of cotinine metabolism.
Foth
H
H
Zentrum für Pharmakologie und Toxikologie, Universität Göttingen.
Aubrecht
J
J
Höhne
M
M
Walther
U I
UI
Kahl
G F
GF
D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D002478:Cells, Cultured; D003367:Cotinine / Q000031:analogs & derivatives* / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL / Q000378:metabolism; D009538:Nicotine / Q000493:pharmacokinetics*; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains / Q000378:metabolism
C001605:cotinine-N-oxide; D009538:Nicotine; D003577:Cytochrome P-450 Enzyme System; D003367:Cotinine; D010634:Phenobarbital