Nwosu C G, Godin C S, Houdi A A, Damani L A, Crooks P A
College of Pharmacy, Division of Medicinal Chemistry and Pharmacognosy, University of Kentucky, Lexington 40536-0083.
J Pharm Pharmacol. 1988 Dec;40(12):862-9. doi: 10.1111/j.2042-7158.1988.tb06289.x.
The S-(-)- and R-(+)-nicotine isomers were administered subcutaneously via Alzet osmotic pumps to male Hartley guinea-pigs (n = 5 with each isomer) over a 23-day period. Estimated dosage rate throughout the experiment was 0.6 mg-1. Urine samples were collected over this time and the levels of urinary oxidative and N-methylated nicotine metabolites were measured by cation-exchange HPLC analysis. S-(-)-Nicotine formed only oxidative metabolites, whereas the R-(+)-isomer formed both oxidative and N-methylated metabolites. 3'-Hydroxycotinine and nicotine-1'-oxide were major metabolites of both enantiomers; cotinine and nornicotine were only minor metabolites. The major N-methylated metabolite of R-(+)-nicotine was N-methylnicotinium ion; N-methylcotininium ion and N-methylnornicotinium ion were also identified as metabolites of this nicotine isomer. Total N-methylated quaternary ammonium metabolites accounted for 15 to 20% of the administered dose of R-(+)-nicotine. An interesting enantioselective reduction in the percent of oxidative urinary metabolites formed S-(-)-nicotine was observed over 23 days. This may indicate the enantioselective induction of an uncharacterized metabolic pathway for this nicotine isomer.
通过Alzet渗透泵将S-(-)-和R-(+)-尼古丁异构体皮下注射给雄性Hartley豚鼠（每种异构体n = 5），持续23天。整个实验期间估计剂量率为0.6毫克/天。在此期间收集尿液样本，并通过阳离子交换HPLC分析测量尿液中氧化型和N-甲基化尼古丁代谢物的水平。S-(-)-尼古丁仅形成氧化代谢物，而R-(+)-异构体既形成氧化代谢物又形成N-甲基化代谢物。3'-羟基可替宁和尼古丁-1'-氧化物是两种对映体的主要代谢物；可替宁和去甲烟碱只是次要代谢物。R-(+)-尼古丁的主要N-甲基化代谢物是N-甲基烟碱离子；N-甲基可替宁离子和N-甲基去甲烟碱离子也被鉴定为该尼古丁异构体的代谢物。总的N-甲基化季铵代谢物占所给予R-(+)-尼古丁剂量的15%至20%。在23天内观察到S-(-)-尼古丁形成的氧化型尿液代谢物百分比存在有趣的对映体选择性降低。这可能表明该尼古丁异构体存在一种未表征代谢途径的对映体选择性诱导。
