SPECIFIC ANTIBODY FAB FRAGMENTS ON DESIPRAMINE PHARMACOKINETICS IN THE RAT IN-VIVO AND IN THE ISOLATED, PERFUSED LIVER

Drug-specific antibody fragments, which can reverse tricyclic antidepr essant toxicity in rats, represent a potential clinical treatment for tricyclic antidepressant overdose in humans. To delineate the pharmaco kinetic mechanisms, we studied the effects of a high-affinity, drug-sp ecific Fab fragment on desipramine (DMI) disposition in rats and on DM I kinetics in the isolated, perfused rat liver. These studies were per formed at high DMI and Fab doses, with Fab administered at the time of peak DMI toxicity, to simulate the treatment of overdose. Rats receiv ed 20 mg/kg DMI intravenously over 30 min followed in 10 min by DMI-sp ecific ovine polyclonal Fab (DMI-Fab) or nonspecific human Fab (contro l-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 c urve increased by more than 3-fold. The steady-state volume of distrib ution was decreased by 90% and total body clearance was decreased by 7 0% after DMI-Fab administration compared with control-fab. Renal clear ance increased by 72% after DMI-Fab and total renal excretion of DMI i ncreased by 7-fold due to the much higher serum DMI concentration. Nin ety-four percent of DMI-Fab excretion and 87% of DMI excretion occurre d in the first 12 h. The percent of DMI bound in urine was markedly in creased 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 wi th DMI alone, DMI and DMI-Fab or DMI and control-fab. DMI-Fab dramatic ally 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 li ver 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 F ab fragments to a clinically important drug overdose and one with a mu ch higher toxic dose than those studied previously.