ENANTIOSELECTIVE METABOLISM DURING CONTINUOUS ADMINISTRATION OF S-(-)-NICOTINE AND R-(+)-NICOTINE ISOMERS TO GUINEA-PIGS
ENANTIOSELECTIVE METABOLISM DURING CONTINUOUS ADMINISTRATION OF S-(-)-NICOTINE AND R-(+)-NICOTINE ISOMERS TO GUINEA-PIGS
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DOI：
10.1111/j.2042-7158.1988.tb06289.x
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发表时间：
1988-12-01
影响因子：
3.3
通讯作者：
CROOKS, PA
中科院分区：
文献类型：
--
作者：
NWOSU, CG;GODIN, CS;CROOKS, PA
雄性Hartley豚鼠(n=5)皮下注射S-(-)-和R-(+)-尼古丁异构体，每种异构体23天。整个实验的估计剂量率为0.6 mg-1。在此期间收集尿样，并用阳离子交换高效液相色谱法测定尿中氧化和N-甲基化尼古丁代谢物的水平。S-(-)-尼古丁只形成氧化代谢物，而R-(+)-异构体既形成氧化代谢物，又形成N-甲基化代谢物。3-羟可替宁和烟碱-1‘-氧化物是两种对映体的主要代谢产物，可替宁和去甲烟碱是次要代谢产物。R-(+)-烟碱的主要N-甲基化代谢物为N-甲基烟碱，N-甲基烟碱和N-甲基去甲烟碱离子也是该烟碱异构体的代谢物。总的N-甲基化季铵代谢物占R-(+)-尼古丁给药剂量的15%至20%。在23天的时间里，观察到S-(-)-尼古丁形成的氧化尿代谢物的百分比有一个有趣的对映选择性降低。这可能表明对映体选择性地诱导了这种尼古丁异构体的一条未知的代谢途径。
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; N-methylcotininium and N-methylnornicotinium ion were also identified as metabolites of this nicotine isomer. Total N-methylated quarternary 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 from S-(-)-nicotine was observed over 23 days. This may indicate the enantioselective induction of an uncharacterized metabolic pathway for this nicotine isomer.