Greenblatt D J, Miller L G, Shader R I
Department of Psychiatry, Tufts University School of Medicine, Boston, MA.
J Clin Psychiatry. 1987 Oct;48 Suppl:4-11.
The 7-nitrobenzodiazepine derivative clonazepam is initially biotransformed by nitroreduction, followed by acetylation. Neither the amino- nor the acetamido- metabolites appear to have important pharmacologic activity. Clonazepam elimination half-life falls in the range of 20 to 80 hours, but means within the population and variance are not well defined. Absorption of orally administered clonazepam is 80% or more. In experimental studies, clonazepam appears to diffuse passively from plasma into brain, with a constant brain-plasma concentration ratio. The drug disappears in a parallel fashion from both brain and plasma, with no evidence of sequestration in brain tissue. Clonazepam has a relatively high molar affinity for the benzodiazepine receptor in vitro, and the fractional extent of benzodiazepine receptor occupation by clonazepam in vivo is directly and predictably related to the drug's concentration in brain tissue. Acute behavioral effects are in turn directly related to the extent of receptor occupancy. Compared to other benzodiazepines, the reportedly unique clinical properties of clonazepam are neither associated with unusual/unexpected pharmacokinetic properties or with a qualitatively different in vivo interaction with the presumed benzodiazepine binding site.
7-硝基苯二氮䓬衍生物氯硝西泮最初通过硝基还原进行生物转化，随后进行乙酰化。氨基代谢物和乙酰氨基代谢物似乎均无重要的药理活性。氯硝西泮的消除半衰期在20至80小时范围内，但总体人群中的平均值和方差尚无明确定义。口服氯硝西泮的吸收率为80%或更高。在实验研究中，氯硝西泮似乎从血浆被动扩散至脑内，脑-血浆浓度比恒定。药物以平行方式从脑和血浆中消失，没有证据表明其在脑组织中潴留。氯硝西泮在体外对苯二氮䓬受体具有相对较高的摩尔亲和力，体内氯硝西泮占据苯二氮䓬受体的分数程度与药物在脑组织中的浓度直接且可预测地相关。急性行为效应又与受体占据程度直接相关。与其他苯二氮䓬类药物相比，据报道氯硝西泮独特的临床特性既与异常/意外的药代动力学特性无关，也与体内与假定的苯二氮䓬结合位点的定性不同的相互作用无关。
