Drug-specific antibody fragments, which can reverse tricyclic antidepressant toxicity in rats, represent a potential clinical treatment for tricyclic antidepressant overdose in humans. To delineate the pharmacokinetic mechanisms, we studied the effects of a high-affinity, drug-specific Fab fragment on desipramine (DMI) disposition in rats and on DMI kinetics in the isolated, perfused rat liver. These studies were performed at high DMI and Fab doses, with Fab administered at the time of peak DMI toxicity, to simulate the treatment of overdose. Rats received 20 mg/kg DMI intravenously over 30 min followed in 10 min by DMI-specific ovine polyclonal Fab (DMI- Fab) or nonspecific human Fab (control-Fab) (1.1 g/kg; molar Fab-to-DMI ratio, 0.34) intravenously over 20 min. The serum DMI concentration increased by 50-fold 5 min after DMI-Fab administration. The mean area under the serum concentration-time curve increased by more than 3-fold. The steady-state volume of distribution was decreased by 90% and total body clearance was decreased by 70% after DMI-Fab administration compared with control-Fab. Renal clearance increased by 72% after DMI-Fab and total renal excretion of DMI increased by 7-fold due to the much higher serum DMI concentration. Ninety-four percent of DMI-Fab excretion and 87% of DMI excretion occurred in the first 12 h. The percent of DMI bound in urine was markedly increased by DMI-Fab (87.1 vs. 19.1%), as was the molar ratio of DMI to DMI-Fab in urine (0.75 vs. 0.08). Isolated rat livers were perfused with DMI alone, DMI and DMI-Fab or DMI and control-Fab. DMI-Fab dramatically reduced DMI clearance by 30-fold. Excretion of DMI in bile after DMI-Fab was decreased by 3-fold. DMI- Fab extraction by the perfused liver was negligible. These data provide a pharmacokinetic rationale for the previously observed efficacy of DMI- specific Fab in reversing DMI toxicity in rats, most important, a large reduction in the volume of distribution of DMI. A marked reduction in hepatic DMI extraction was balanced in part by enhanced renal excretion of DMI due to binding by DMI-Fab and excretion of the bound complex. These data extend previous observations regarding the pharmacokinetic effects of drug-specific Fab fragments to a clinically important drug overdose and one with a much higher toxic dose than those studied previously.
|Original language||English (US)|
|Number of pages||7|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1995|