Anelli M, Bizzi A, Caccia S, Codegoni A M, Fracasso C, Garattini S
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
J Pharm Pharmacol. 1992 Aug;44(8):696-8. doi: 10.1111/j.2042-7158.1992.tb05500.x.
The present study aimed to establish the role of the metabolite norfluoxetine in the anorectic activity of fluoxetine, and to relate the anorectic doses (ED50) to the brain concentrations of the parent drug and its metabolite. Fluoxetine showed anorectic activity at increasing intraperitoneal doses (ED50 = 39.1, 34.7 and 21.7 mumol kg-1 in mouse, rat and guinea-pig, respectively) and norfluoxetine was slightly more active (24.3, 22.9 and 19.1 mumol kg-1, respectively) in all three species. In terms of maximum concentration (Cmax) and area under the curve (AUC) within the experimental period (0-90 min), brain concentrations varied widely and were poorly related to the dose; guinea-pig appeared to be much more sensitive to fluoxetine than was mouse or rat. Administered norfluoxetine was present in the brain of the three species in approximately the same order as fluoxetine, i.e. lower in guinea-pig than in mouse or rat. The Cmax and AUC of norfluoxetine after fluoxetine administration was 50-60% of the values after an equiactive dose of norfluoxetine in mouse and guinea-pig, and more than 80% in rat.
本研究旨在确定代谢物去甲氟西汀在氟西汀厌食活性中的作用，并将厌食剂量（ED50）与母体药物及其代谢物的脑浓度相关联。氟西汀在腹腔注射剂量增加时表现出厌食活性（在小鼠、大鼠和豚鼠中，ED50分别为39.1、34.7和21.7 μmol kg-1），而去甲氟西汀在所有三个物种中活性略高（分别为24.3、22.9和19.1 μmol kg-1）。就实验期间（0 - 90分钟）的最大浓度（Cmax）和曲线下面积（AUC）而言，脑浓度差异很大，且与剂量的相关性较差；豚鼠似乎比小鼠或大鼠对氟西汀更敏感。给药后的去甲氟西汀在三个物种脑中的含量顺序与氟西汀大致相同，即豚鼠脑中的含量低于小鼠或大鼠。在小鼠和豚鼠中，氟西汀给药后去甲氟西汀的Cmax和AUC为等活性剂量去甲氟西汀给药后值的50 - 60%，在大鼠中则超过80%。
