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 seru m primarily by alpha-1-acid glycoprotein. The present study examined t he 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 alph a-1-acid glycoprotein is significantly elevated over normal. The pharm acokinetic disposition was characterized after i.v. and i.p. injection s in transgenic and control mice. In transgenic mice, there were signi ficant decreases in the serum unbound fraction (0.62 +/- 0.38 vs, 2.48 +/- 0.43%), V-d(9.0 +/- 2.5 vs. 22.4 +/- 3.2 liters/kg), T-1/2 (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 altera tions in systemic clearance (204.7 +/- 56.1 vs. 292.8 +/- 58.4 ml/min/ kg) compared to control values. The antidepressant activity of imipram ine was measured by a swimming-immobility test 30 min after either imi pramine (30 mg/kg i.p.) or saline treatment. After saline treatment, t here were no significant differences in the duration of swimming despa ir between transgenic (183 +/- 24 sec) and control (175 +/- 12 sec) mi ce. Imipramine treatment resulted in reductions in the duration of imm obility in both transgenic (130 +/- 21 sec) and control (54 +/- 33 sec ) mice. The extent of reduction was significantly less in transgenic a nimals than in control animals. These alterations in the antidepressan t action appeared to correlate with the unbound drug concentration but not with the total drug concentration.