Wang Jun-Sheng, Markowitz John S, Donovan Jennifer L, Devane C Lindsay
Laboratory of Drug Disposition and Pharmacogenetics, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina 49425, USA.
Addict Biol. 2005 Jun;10(2):127-9. doi: 10.1080/13556210500122995.
The ABCB1 gene transporter P-glycoprotein (P-gp) exists in the blood-brain barrier (BBB) and placenta and limits many drugs passing through the BBB and placenta. Several recent studies have raised confounding results regarding the roles of P-gp in nicotine disposition. To ascertain this question, we examined the effects of nicotine and its major oxidative metabolite, cotinine, on ATPase activity using P-gp containing membranes, in which nicotine and cotinine-stimulated inorganic Pi was used as a marker of the binding affinity of nicotine and cotinine to P-gp. At concentrations ranging from 5 to 1000 microm, both nicotine and cotinine produced modest stimulative effects on ATPase activity in the P-gp containing membrane. The Clint values of nicotine and cotinine were 0.01 and 0.007 minute(-1) x 10(-3), respectively. The positive control, verapamil, at concentrations ranging from 1 to 100 microm, created apparent stimulative effects on ATPase activity, with a Clint value of 1.7 minute(-1) x 10(-3), consistent with previously reported results. The results of the current study suggest that nicotine and cotinine were not actively transported by P-gp out of the cells. The observed carrier-mediated nicotine transport in various cell lines may be mediated by other transporter proteins but not P-gp.
ABCB1基因转运体P-糖蛋白（P-gp）存在于血脑屏障（BBB）和胎盘中，会限制许多药物通过血脑屏障和胎盘。最近的几项研究就P-gp在尼古丁处置中的作用得出了相互矛盾的结果。为了确定这个问题，我们使用含P-gp的膜，研究了尼古丁及其主要氧化代谢物可替宁对ATP酶活性的影响，其中尼古丁和可替宁刺激产生的无机磷被用作尼古丁和可替宁与P-gp结合亲和力的标志物。在5至1000微摩尔的浓度范围内，尼古丁和可替宁对含P-gp膜中的ATP酶活性均产生适度的刺激作用。尼古丁和可替宁的肝清除率值分别为0.01和0.007分钟-1×10-3。阳性对照维拉帕米在1至100微摩尔的浓度范围内，对ATP酶活性产生明显的刺激作用，肝清除率值为1.7分钟-1×10-3，与先前报道的结果一致。当前研究结果表明，尼古丁和可替宁不会被P-gp主动转运出细胞。在各种细胞系中观察到的载体介导的尼古丁转运可能由其他转运蛋白介导，而非P-gp。
