Bisaga Adam, Kos Tomasz, Wójcikowski Jacek, Daniel Wladyslawa Anna, Popik Piotr
Division on Substance Abuse, Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA.
Drug Alcohol Depend. 2008 May 1;95(1-2):147-51. doi: 10.1016/j.drugalcdep.2008.01.007. Epub 2008 Mar 6.
Consistent with their antagonistic actions at N-methyl-D-aspartate type glutamate receptors, dextromethorphan (DXM) and its metabolite, dextrorphan (DXT) decrease the intensity of opioid withdrawal syndrome. Since quinidine (QND) affects CYP2D6-mediated metabolism and P-glycoprotein governed transport, we sought to determine whether co-treatment with QND would affect brain levels of DXM and DXT as well as the effect of these compounds on opioid withdrawal syndrome in mice. We found that DXM dose dependently inhibited the intensity of opioid withdrawal syndrome and that there was a tendency for a further decrease when QND was co-administered with DXM. Administration of 30 mg/kg of DXM resulted in higher brain levels of DXM and DXT than administration of 10 mg/kg of DXM, but much lower DXT levels than that produced by 30 mg/kg of DXT. Co-treatment with QND resulted in higher brain levels of DXM (but not DXT) suggesting that QND produces an increase in the brain availability of DXM. In summary, brain levels of DXM were inversely correlated with the intensity of opioid withdrawal syndrome. QND induced increased brain levels of DXM tend to attenuate the intensity of opioid withdrawal syndrome. We suggest that it is DXM, rather than DXT, that is responsible for the attenuating effect on the intensity of opioid withdrawal syndrome, and that the beneficial action of QND on the effect of DXM should be more pronounced in humans.
与右美沙芬（DXM）及其代谢产物右啡烷（DXT）对N-甲基-D-天冬氨酸型谷氨酸受体的拮抗作用一致，它们可降低阿片类药物戒断综合征的强度。由于奎尼丁（QND）会影响细胞色素P450 2D6介导的代谢以及P-糖蛋白调控的转运，我们试图确定QND联合用药是否会影响小鼠脑中DXM和DXT的水平，以及这些化合物对阿片类药物戒断综合征的影响。我们发现DXM剂量依赖性地抑制阿片类药物戒断综合征的强度，并且当QND与DXM联合给药时，有进一步降低的趋势。给予30mg/kg的DXM导致脑中DXM和DXT的水平高于给予10mg/kg的DXM，但DXT水平远低于30mg/kg的DXT所产生的水平。与QND联合治疗导致脑中DXM（而非DXT）水平升高，这表明QND使DXM在脑中的可利用性增加。总之，脑中DXM的水平与阿片类药物戒断综合征的强度呈负相关。QND诱导脑中DXM水平升高往往会减弱阿片类药物戒断综合征的强度。我们认为，对阿片类药物戒断综合征强度起减弱作用的是DXM而非DXT，并且QND对DXM作用的有益影响在人类中可能更为显著。
