Steady-state kinetics of imipramine in transgenic mice with elevated serum AAG levels.
OBJECTIVE
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.
College of Pharmacy, University of South Carolina, Columbia 29208, USA.
J W
JW
Holladay
M J
MJ
Dewey
S D
SD
Yoo
D000818:Animals; D000928:Antidepressive Agents / Q000493:pharmacokinetics*; D001692:Biological Transport; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D003891:Desipramine / Q000097:blood / Q000378:metabolism; D005260:Female; D007099:Imipramine / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009961:Orosomucoid / Q000032:analysis*; D011485:Protein Binding
D000928:Antidepressive Agents; D001798:Blood Proteins; D009961:Orosomucoid; D007099:Imipramine; D003891:Desipramine