Kyerematen G A, Owens G F, Chattopadhyay B, deBethizy J D, Vesell E S
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey 17033.
Drug Metab Dispos. 1988 Nov-Dec;16(6):823-8.
Interpretation of sex differences in nicotine metabolism and disposition in rats required studies both in vivo and in vitro to provide both metabolic and pharmacokinetic data. In each of four rat strains studied in vitro, males metabolized nicotine faster than did females. In Sprague-Dawley rats, studies of nicotine kinetics after a single iv dose of [14C]nicotine revealed a larger nicotine volume of distribution in females than in males. A prolonged plasma nicotine half-life in females balanced the larger volume of distribution, so that no sex difference appeared in plasma clearance of nicotine. Nevertheless, sex differences in nicotine metabolism are indicated inasmuch as 1) females had lower plasma cotinine concentrations than did males; 2) urinary recoveries of nicotine were higher in female than in male rats; 3) total urinary output of nicotine metabolites was higher in male than female rats, consistent with the enhanced N- and C-oxidation of nicotine by male rats observed in vitro. In female rats the reduced rate of nicotine metabolism, as well as a larger volume of distribution of nicotine, explains in part the reported increased lethality of female compared with male rats.
对大鼠尼古丁代谢和处置过程中性别差异的解读需要进行体内和体外研究，以提供代谢和药代动力学数据。在所研究的四种大鼠品系中的每一种中，体外实验显示雄性大鼠代谢尼古丁的速度比雌性大鼠快。在斯普拉格-道利大鼠中，单次静脉注射[14C]尼古丁后对尼古丁动力学的研究表明，雌性大鼠的尼古丁分布容积比雄性大鼠大。雌性大鼠较长的血浆尼古丁半衰期平衡了较大的分布容积，因此在尼古丁的血浆清除率方面未出现性别差异。然而，尼古丁代谢存在性别差异，具体表现为：1）雌性大鼠的血浆可替宁浓度低于雄性大鼠；2）雌性大鼠尿液中尼古丁的回收率高于雄性大鼠；3）雄性大鼠尼古丁代谢物的总尿量高于雌性大鼠，这与体外观察到的雄性大鼠尼古丁N-氧化和C-氧化增强一致。在雌性大鼠中，尼古丁代谢速率降低以及尼古丁分布容积较大，部分解释了与雄性大鼠相比雌性大鼠致死率增加的报道。
