Benowitz N L, Jacob P, Fong I, Gupta S
Division of Clinical Pharmacology and Experimental Therapeutics, San Francisco General Hospital Medical Center, California.
J Pharmacol Exp Ther. 1994 Jan;268(1):296-303.
The objectives of this study were to 1) quantitatively assess human exposure to various metabolites of nicotine, 2) examine the influence of inhalation vs. transdermal administration on the patterns of nicotine metabolism, and 3) assess the extent of recovery of nicotine as various metabolites in people whose systemic intake of nicotine has been measured. Twelve smokers were studied while smoking cigarettes and while receiving transdermal nicotine. Urinary excretion of nicotine and eight of its metabolites was measured under steady state conditions. The systemic intake of nicotine in these subjects was determined using plasma concentrations and intravenous clearance data, so the percentage of their daily dose of nicotine excreted as various metabolites could be computed. The major findings of the study are as follows: 1) a high percentage (averaging 88%) of a systemic dose of nicotine can be accounted for by measurement of nicotine and its metabolites; 2) the pattern of metabolism is generally similar when nicotine is inhaled or absorbed transdermally; 3) while there is considerable interindividual variability in the pattern of metabolism, the pattern is consistent for an individual; and 4) within individuals, the extent of conjugation of nicotine and cotinine is highly correlated, but neither is correlated with the extent of conjugation of 3'-hydroxycotinine. This suggests that similar enzymes are involved in the conjugation of nicotine and cotinine, and that a different enzyme may be involved in the conjugation of 3'-hydroxycotinine.
1）定量评估人体对尼古丁各种代谢物的暴露情况；2）研究吸入给药与经皮给药对尼古丁代谢模式的影响；3）评估在已测量尼古丁全身摄入量的人群中，尼古丁作为各种代谢物的恢复程度。对12名吸烟者在吸烟时以及接受经皮尼古丁给药时进行了研究。在稳态条件下测量了尼古丁及其8种代谢物的尿排泄量。利用血浆浓度和静脉清除率数据确定了这些受试者的尼古丁全身摄入量，从而可以计算出他们每日剂量的尼古丁以各种代谢物形式排泄的百分比。该研究的主要发现如下：1）通过测量尼古丁及其代谢物，可以解释全身剂量尼古丁的很大一部分（平均88%）；2）吸入或经皮吸收尼古丁时，代谢模式通常相似；3）虽然代谢模式存在相当大的个体间差异，但个体的代谢模式是一致的；4）在个体内部，尼古丁和可替宁的结合程度高度相关，但两者均与3'-羟基可替宁的结合程度无关。这表明参与尼古丁和可替宁结合的酶相似，而参与3'-羟基可替宁结合的酶可能不同。
