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Vol. 291, Issue 3, 1196-1203, December 1999
Division of Clinical Pharmacology and Experimental Therapeutics, We previously reported that the metabolism of cotinine,
the proximate metabolite of nicotine, is significantly slower in black than in white cigarette smokers. To understand why the
metabolism of nicotine and cotinine might differ between blacks and
whites, we studied the pattern of nicotine metabolism in blacks and
whites. One hundred eight healthy smokers (51 blacks and 57 whites), of similar age, gender distribution, and smoking history, received an i.v.
infusion of deuterium-labeled nicotine and cotinine. The clearance of
cotinine, the fractional conversion of nicotine to cotinine, and the
metabolic clearance of nicotine to cotinine were significantly lower in
blacks than in whites. Blacks excreted significantly less nicotine as
nicotine-N-glucuronide and less cotinine as
cotinine-N-glucuronide than whites, but there was no
difference in the excretion of
3'-hydroxycotinine-O-glucuronide. Nicotine and cotinine
glucuronidation appeared to be polymorphic, with evidence of slow and
fast N-glucuronide formers among blacks but was unimodal
with fast conjugators only among whites. Other findings of note
included the demonstration of a significant correlation between the
distribution volumes of nicotine and cotinine with lean body mass:
there was a smaller distribution volume and a shorter half-life for
cotinine in women than in men and a smaller volume of distribution of
cotinine in blacks than in whites. We conclude that the metabolism of
cotinine is slower in blacks than in whites because of both slower
oxidative metabolism of nicotine to cotinine (presumably via
cytochrome P-450 2A6) and slower
N-glucuronidation. Ethnic differences in the metabolism
of other drugs undergoing N-glucuronidation should be studied.
0022-3565/99/2913-1196$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics
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