Altered disposition and antidepressant activity of imipramine in transgenic mice with elevated alpha-1-acid glycoprotein.
Imipramine is a tricyclic antidepressant known to be bound in the serum primarily by alpha-1-acid glycoprotein. The present study examined the effect of changes in serum alpha-1-acid glycoprotein levels on the pharmacokinetics and antidepressant activity of the drug by utilizing a novel set of transgenic mice in which the steady-state level of alpha-1-acid glycoprotein is significantly elevated over normal. The pharmacokinetic disposition was characterized after i.v. and i.p. injections in transgenic and control mice. In transgenic mice, there were significant decreases in the serum unbound fraction (0.62+/- 0.38 vs.2.48 +/- 0.43%), Vd (9.0 +/- 2.5 vs. 22.4 +/- 3.2 liters/kg), T1/2 (35.0 +/- 7.6 vs. 65.3 +/- 7.6 min) and fraction of dose excreted unchanged in urine (0.14 +/- 0.07 vs. 0.70 +/- 0.20%) with no significant alterations in systemic clearance (204.7 +/- 56.1 vs. 292.8 +/- 58.4 ml/min/kg) compared to control values. The antidepressant activity of imipramine was measured by a swimming-immobility test 30 min after either imipramine (30 mg/kg i.p.) or saline treatment. After saline treatment, there were no significant differences in the duration of swimming despair between transgenic (183 +/- 24 sec) and control (175 +/- 12 sec) mice. Imipramine treatment resulted in reductions in the duration of immobility in both transgenic (130 +/- 21 sec) and control (54 +/- 33 sec) mice. The extent of reduction was significantly less in transgenic animals than in control animals. These alterations in the antidepressant action appeared to correlate with the unbound drug concentration but not with the total drug concentration.
Yoo
S D
SD
College of Pharmacy, University of South Carolina, Columbia, USA.
Holladay
J W
JW
Fincher
T K
TK
Baumann
H
H
Dewey
M J
MJ
D000818:Animals; D001667:Binding, Competitive; D005260:Female; D006023:Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D007099:Imipramine / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects*; D013550:Swimming
D006023:Glycoproteins; D007099:Imipramine