Kyerematen G A, Taylor L H, deBethizy J D, Vesell E S
Department of Pharmacology, Pennsylvania State University, College of Medicine, Hershey 17033.
Drug Metab Dispos. 1988 Jan-Feb;16(1):125-9.
A new radiometric assay for nicotine and 12 of its metabolites disclosed that plasma nicotine and cotinine t1/2 beta were independent of dose after single intraarterial nicotine doses of 0.1, 0.5, or 1.0 mg/kg. At high doses, nicotine AUC and clearance tended to exhibit a small degree of dose dependency. The longest lived metabolites, cotinine-N-oxide and a previously unidentified metabolite now revealed to be allohydroxydemethylcotinine, persisted for 96 hr after nicotine injection, whereas cotinine was detected for only 48 hr. Cotinine, formerly considered the longest lived nicotine metabolite, serves widely as the most sensitive indicator of prior exposure to small concentrations of nicotine. The present studies disclose new, longer lasting metabolites that may perform this function more sensitively, at least in the rat. At the 3 doses of nicotine administered, plasma nicotine half-life ranged from 0.9 to 1.1 hr; total body clearance of nicotine ranged from 2.9 to 3.9 liters.hr-1.kg-1; and apparent volume of distribution of nicotine from 4.7 to 5.7 liters.kg-1. Also at these 3 doses, mean half-lives of urinary excretion of cotinine, cotinine-N-oxide, and allohydroxydemethylcotinine ranged from 4.8 to 5.3 hr, from 7.9 to 8.2 hr, and from 9.9 to 11.0 hr, respectively.
一种针对尼古丁及其12种代谢物的新型放射分析方法表明，在单次动脉内注射0.1、0.5或1.0 mg/kg尼古丁后，血浆尼古丁和可替宁的t1/2β与剂量无关。在高剂量时，尼古丁的AUC和清除率往往表现出一定程度的剂量依赖性。寿命最长的代谢物，可替宁 - N - 氧化物和一种现已确定为别羟基去甲基可替宁的先前未鉴定代谢物，在注射尼古丁后持续存在96小时，而可替宁仅被检测到48小时。可替宁以前被认为是寿命最长的尼古丁代谢物，广泛用作先前接触低浓度尼古丁的最敏感指标。目前的研究揭示了新的、持续时间更长的代谢物，至少在大鼠中，它们可能更敏感地发挥这一功能。在给予的3个尼古丁剂量下，血浆尼古丁半衰期为0.9至1.1小时；尼古丁的全身清除率为2.9至3.9升·小时-1·千克-1；尼古丁表观分布容积为4.7至5.7升·千克-1。同样在这3个剂量下，可替宁、可替宁 - N - 氧化物和别羟基去甲基可替宁的尿排泄平均半衰期分别为4.8至5.3小时、7.9至8.2小时和9.9至11.0小时。
