PURPOSE: The effect of elevated serum alpha-1-acid glycoprotein (AAG) concentrations on the steady-state serum and brain levels of imipramine and its metabolite desipramine was assessed. This was approached using a novel strain of transgenic mice whose basal endogenous serum AAG levels were 8.6-fold elevated over normal. METHODS: Imipramine was administered by s.c. infusion or i.p., injection into transgenic and control mice. After drug administration, serum and whole brain were harvested and analyzed for imipramine and desipramine concentrations. Equilibrium dialysis was performed to determine the extent of imipramine protein binding in transgenic and control sera. Serum and brain samples were analyzed for imipramine and desipramine content by an established HPLC method with UV detection. RESULTS: At steady-state, the mean serum imipramine concentration was significantly higher in transgenic mice than in control mice (859.0 vs. 319.9 ng/ml). In contrast, the mean steady-state brain imipramine concentration was significantly lower in transgenic mice (3,862.6 vs. 7,307.7 ng/g). Similarly, in transgenic mice, the mean steady-state serum desipramine concentration was significantly higher (176.7 vs. 39.0 ng/ml) while the mean brain desipramine concentration was lower (243.0 vs. 393.5 ng/g). The serum unbound fraction of imipramine was 3-fold lower in transgenic mice (0.03 vs. 0.09). CONCLUSIONS: Elevated serum AAG impedes the transport of imipramine and desipramine into the brain. Further, in the presence of elevated serum AAG levels, imipramine and desipramine concentrations in the brain did not correlate with their respective concentrations in the serum.
PURPOSE: The effect of elevated serum alpha-1-acid glycoprotein (AAG) concentrations on the steady-state serum and brain levels of imipramine and its metabolite desipramine was assessed. This was approached using a novel strain of transgenic mice whose basal endogenous serum AAG levels were 8.6-fold elevated over normal. METHODS:Imipramine was administered by s.c. infusion or i.p., injection into transgenic and control mice. After drug administration, serum and whole brain were harvested and analyzed for imipramine and desipramine concentrations. Equilibrium dialysis was performed to determine the extent of imipramine protein binding in transgenic and control sera. Serum and brain samples were analyzed for imipramine and desipramine content by an established HPLC method with UV detection. RESULTS: At steady-state, the mean serum imipramine concentration was significantly higher in transgenic mice than in control mice (859.0 vs. 319.9 ng/ml). In contrast, the mean steady-state brain imipramine concentration was significantly lower in transgenic mice (3,862.6 vs. 7,307.7 ng/g). Similarly, in transgenic mice, the mean steady-state serum desipramine concentration was significantly higher (176.7 vs. 39.0 ng/ml) while the mean brain desipramine concentration was lower (243.0 vs. 393.5 ng/g). The serum unbound fraction of imipramine was 3-fold lower in transgenic mice (0.03 vs. 0.09). CONCLUSIONS: Elevated serum AAG impedes the transport of imipramine and desipramine into the brain. Further, in the presence of elevated serum AAG levels, imipramine and desipramine concentrations in the brain did not correlate with their respective concentrations in the serum.