Effect of desmethylimipramine on tissue distribution and anorectic activity of chlorphentermine in rats

The anorectic effect and tissue distribution of chlorphentermine (CP) have been measured in the presence and absence of desmethyl-imipramine (DMI) in rats, following the finding that DMI was a potent displacer of CP from lung tissue in vitro. CP (10 mg/kg) produced significant anorexia for 4–5 hours after intraperitoneal administration and reduced food intake in a manner similar to that of fenfluramine; that is, CP decreased the rate of eating without affecting onset of eating. DMI caused dose-related changes in CP-induced anorexia; 5 mg/kg DMI inhibited the effects of CP (10 mg/kg) while, with 7.5 mg/kg DMI, there was potentiation. DMI (7.5 mg/kg) significantly (P<0.05) decreased CP (10 mg/kg) concentrations in lung tissue and increased concentrations in brain, liver and blood for up to four hours after treatment, but did not affect kidney or skeletal muscle levels. The CP tissue concentration-time profiles for liver, brain and kidney were significantly different in the presence and absence of DMI, suggesting non-linear kinetics, probably due to saturable tissue binding. Using a simple model to describe eating behaviour, the increased anorexia was found to be linearly related to the higher brain levels of CP seen in the presence of DMI.