Facilitation of imipramine efflux from the brain by systemic specific antibodies.
1. This study investigated the capacity of circulating anti-tricyclic antidepressant (TCA) IgG to increase the efflux of imipramine (Imip) from the rat brain. 2. A tracer amount of [3H]-Imip (40 pmol) was injected into the cerebral lateral ventricle and its efflux was determined in control rats and in rats given anti-TCA antibody. The monoclonal anti-TCA IgG1 was injected i.v. 48 h before Imip at 4 IgG:Imip molar ratios (10, 100, 1000 and 10,000). The [3H]-Imip in arterial and venous plasma was measured for up to 60 min, and in the brain and peripheral organs (heart, liver, lung, kidney) 5 and 60 min after Imip injection. 3. The arterial plasma concentration of Imip in control rats was significantly higher (26.7 +/- 2.1 pM) than the venous one (17.7 +/- 2.0 pM) at 5 min, indicating that Imip released from brain becomes distributed in peripheral tissues. These concentrations were not significantly different at 60 min suggesting that Imip was, at this time, redistributing from extravascular tissues to the blood. In rats given anti-TCA IgG, any Imip leaving the brain was immediately bound by the circulating antibody at 5 min. This greatly reduced the Imip in the heart (63.9%) and lung (61.3%) at the highest IgG:Imip ratio. The brain Imip was markedly lower at 60 min (31.5% with an IgG Imip ratio of 1000 and 57.5% at a ratio of 10,000). The two lowest IgG:Imip ratios had less effect on the plasma Imip because of the relative low affinity of the anti-TCA IgG (3.8 x 10(7) M-1). 4. These data indicate that the anti-TCA IgG facilitated the efflux of Imip from the brain, even though these antibodies cannot cross the blood-brain barrier. This may be an efficient system for increasing drug organ clearance, as more than half the Imip in the brain was actively removed by the antibody in 1 h.
Ragusi
C
C
INSERM U26, Hôpital Fernand Widal, Paris, France.
Boschi
G
G
Rips
R
R
Scherrmann
J M
JM
D000818:Animals; D001921:Brain / Q000378:metabolism*; D007099:Imipramine / Q000378:metabolism / Q000493:pharmacokinetics*; D007074:Immunoglobulin G / Q000276:immunology*; D007668:Kidney / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D007074:Immunoglobulin G; D007099:Imipramine