Influence of various combinations of specific antibody dose and affinity on tissue imipramine redistribution

Abstract

This study was designed to evaluate the distribution kinetics of imipramine (Imip) in the brain and the main peripheral organs (heart, kidney, liver and lung) of rats, and to establish the relationship between the redistribution of Imip from these tissues and the immunoreactive capacity (dose and affinity) of anti‐TCA IgG. [3H]‐Imip (1 nmol kg−1 body weight) was injected intravenously 6 min before the i.v. injection of antibodies. At this time, the concentrations of Imip and its main metabolites in plasma were determined. The radioactivity measured corresponded to 91.7% Imip, indicating that the pharmacokinetics reflected essentially Imip. Plasma and tissue Imip contents were measured over the interval 1 to 90 min in control and in treated rats. The antibodies used were a murine monoclonal IgG1 (Ka=3.8 107 M−1) at an IgG1/Imip molar ratio of 1000 (IgG1 1000), and a sheep polyclonal IgG (TAb, Ka=1.3 1010 M−1) at IgG/Imip molar ratios of 1, 10 and 100 (TAb1, TAb10 and TAb100). The anti‐TCA IgG increased the plasma [3H]‐Imip concentrations: the AUC1→60 min for [3H]‐Imip were 4 (IgG1 1000), 9 (TAb1), 33.9 (TAb10) and 41.4 (TAb100) times higher in the treated groups than in the controls. The opposite effect occurred in the brain, heart and lungs, with large, rapid decreases in Imip. The increase in plasma Imip and the decrease in tissue Imip depended on the immunoreactive capacity (NKa) of the antibody, where N=molar concentration of IgG binding sites and Ka=IgG affinity constant. Maximal plasma and tissue redistribution occurred when NKa=33.8×104. Imip redistribution can be controlled using various doses or affinities of specific antibodies, and the resulting rapid, extensive Imip redistribution from the main target organs could be very promising for TCA detoxification. British Journal of Pharmacology (1998) 125, 35–40; doi:10.1038/sj.bjp.0702033

Use of Anti-(+)-Methamphetamine Monoclonal Antibody to Significantly Alter (+)-Methamphetamine and (+)-Amphetamine Disposition in Rats

“…These differences in tissue antibody distribution may also contribute to the observed differences of the anti-METH mAb on (ϩ)-METH tissue concentrations. Regardless of the mechanism, our studies are in agreement with previous studies that show differential effects of anti-drug mAb on tissue drug distribution (Pentel et al, 1991;Ragusi et al, 1998;Proksch et al, 2000).…”

“…Consequently, another factor that could contribute to the increased liver concentration is the decreased Vd of (ϩ)-METH in the presence of mAb, if the liver is part of the central compartment. Other investigators have also reported increased liver concentrations of drugs in rats following treatment with anti-drug mouse mAbs (Pentel et al, 1991;Ragusi et al, 1998).…”

Treatment of Adverse Effects of Excessive Phencyclidine Exposure in Rats with a Minimal Dose of Monoclonal Antibody

“…Other studies have examined the effect of antibody affinity on drug redistribution (Ragusi et al, 1998). In these other studies, high-affinity anti-imipramine mAb (mAb/imipramine ratio of 100:1) was much more efficient than a lowaffinity anti-imipramine mAb (mAb/imipramine ratio 1,000:1) at removing imipramine from the brain.…”

Binding of Imipramine, Dosulepin, and Opipramol to Liposomes for Overdose Treatment

“…Effectively, the liposomes would act as transporters, removing the drug from the fast‐equilibrating organs and redistributing it to slow‐equilibrating ones. This method of redistribution is likely the mechanism for overdose treatment by Fab fragments for digoxin and antidepressants, where the amount of Fab fragments administered is far less than the amount needed to bind the amount of drug present in the entire body 29–33. Evidence for improved pharmacodynamic responses due to redistribution was shown in several animal studies, while human studies revealed an increase in tricyclic antidepressant serum concentrations after fragment administration.…”