Ethnic differences in N-glucuronidation of nicotine and cotinine

We previously reported that the metabolism of cotinine, the proximate metab olite of nicotine, is significantly slower in black than in white cigarette smokers. To understand why the metabolism of nicotine and cotinine might d iffer between blacks and whites, we studied the pattern of nicotine metabol ism in blacks and whites. One hundred eight healthy smokers (51 blacks and 57 whites), of similar age, gender distribution, and smoking history, recei ved an i.v. infusion of deuterium-labeled nicotine and cotinine. The cleara nce of cotinine, the fractional conversion of nicotine to cotinine, and the metabolic clearance of nicotine to cotinine were significantly lower in bl acks than in whites. Blacks excreted significantly less nicotine as nicotin e-N-glucuronide and less cotinine as cotinine-N-glucuronide than whites, bu t there was no difference in the excretion of 3'-hydroxycotinine-O-glucuron ide. Nicotine and cotinine glucuronidation appeared to be polymorphic, with evidence of slow and fast N-glucuronide formers among blacks but was unimo dal with fast conjugators only among whites. Other findings of note include d the demonstration of a significant correlation between the distribution v olumes of nicotine and cotinine with lean body mass: there was a smaller di stribution 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 wh ites because of both slower oxidative metabolism of nicotine to cotinine (p resumably via cytochrome P-450 2A6) and slower N-glucuronidation. Ethnic di fferences in the metabolism of other drugs undergoing N-glucuronidation sho uld be studied.