Influence of dose and route of administration on the kinetics of fluoxetine and its metabolite norfluoxetine in the rat

Fluoxetine (FL) is being used in neuropharmacology as a tool for studying various functional roles of serotoninergic neurons. Its kinetics was studied in rats, a species widely used in neurochemical studies, after IV (2.5–10 mg/kg) and oral (5–20 mg/kg) administration. When injected IV the drug followed apparent first-order kinetics up the 10 mg/kg dose. Its volume of distribution was large and total body clearance was relatively high compared to liver blood flow. The mean elimination half-lives (t_1/2) of FL and its active metabolite norfluoxetine (NFL) were about 5 and 15 h, respectively. The mean blood:plasma concentration ratios of FL and NFL approached unity and plasma protein binding was 85–90% for both compounds. After oral doses the kinetics of FL were complex. At the lowest dose tested (5 mg/kg) the drug was efficiently extracted by the liver (extraction ratio about 60%), resulting in bioavailability of only about 38%. Plasma areas under the curve (AUC) of the metabolite were approximately the same as after IV injection of the same dose; consequently the metabolite-to-parent drug ratio after oral administration (about 5) was approximately twice that after IV injection of FL (about 2.5). At higher doses, however, the oral bioavailability (e.g.C_max and AUC) appeared greater than expected, possibly because of transient saturation of FL first-pass metabolism in the case of the 10 mg/kg dose and concomitant saturation of elimination kinetics at the higher dose (20 mg/kg). The apparent eliminationt_1/2 of FL markedly increased and the metabolite-to-parent drug ratio declined with the higher dose, this also being consistent with saturable elimination. Brain concentrations reflected the plasma kinetics of FL and NFL and the metabolite-to-parent drug ratio varied with dose and time of administration and was modified at the highest dose tested. FL and its metabolite NFL distributed almost evenly in discrete brain areas and subcellular distribution was similar for both compounds. Neurochemical studies of FL should consider the formation of the active metabolite NFL and extrapolation of data across animal species requires consideration of dose dependence in the rat.