Effect of Oxidative Stress on the Pharmacokinetics of Clomipramine in Rats Treated with Ferric-Nitrilotriacetate

Shinji      Kobuchi; Keizo      Fukushima; Hiroaki      Aoyama; Tatsuma      Matsuda; Yukako      Ito; Nobuyuki      Sugioka; Kanji      Takada

Abstract

The effect of oxidative stress (OS) on the pharmacokinetics of clomipramine (CPM), particularly addressing the change of CPM distribution to plasma components, was studied in ferric-nitrilotriacetate-induced oxidative-stress model rats (OS rats). First, CPM pharmacokinetic studies in OS rats were performed using CPM continuous infusion (17.5 μg/min/kg). Plasma concentration of CPM at a steady state in OS rats (0.20 ± 0.02 μg/mL) was significantly lower than that in control rats (0.30 ± 0.02 μg/mL). However, no difference was found in the amounts of CPM in the brains of control rats (1.67 ± 0.13 μg/g) and OS rats (1.63 ± 0.09 μg/g). Both of plasma unbound fraction and distribution to erythrocytes in OS rats were significantly higher than those of control rats. These results suggest that the lower CPM concentration in plasma in OS condition does not induce an inferior pharmacological effect.

Keywords: Pharmacokinetics, protein binding, distribution, lipids, lipoproteins, disease state, oxidative stress, tertiary amines, phobias, histopathological