The pharmacodynamics of desipramine and desmethyldesipramine in rats.

The interrelationships between dose, drug and metabolite levels in the brain, cortex and blood and the magnitude of cortical beta adrenergic receptor downregulation were studied in rats after chronic i.p. administration of desipramine and its demethylated metabolite, desmethyldesipramine. Desipramine and desmethyldesipramine were distributed extensively into the brain and cortex with mean tissue to blood concentration ratios of approximately 10 to 1 and 14 to 1, respectively. Increasing doses of desipramine and desmethyldesipramine resulted in greater than linear increases in the corresponding steady-state trough concentrations of these drugs in brain, cortex and blood. Both drugs caused dose-dependent decreases in cortical beta adrenergic receptor density. The higher doses of desipramine and the highest dose of desmethyldesipramine used in this study caused maximal downregulation of beta adrenergic receptors. No changes were observed in the Kd of cortical beta adrenergic receptors after the administration of the two drugs. The ED50 for desipramine was determined to be 5.10 mg/kg, whereas the ED50 for desmethyldesipramine was 7.71 mg/kg. Nonlinear least-squares fitting of cortical concentration-effect data to the pharmacodynamic Emax model equation after the separate administration of desipramine and desmethyldesipramine generated Emax estimates for desipramine and desmethyldesipramine of approximately 36 and 29%, respectively, and EC50 estimates of 365 and 467 ng/g, respectively. Desmethyldesipramine is capable of maximally downregulating cortical beta adrenergic receptors and could account, in part, for the effect observed after desipramine administration.