*4.3. Exogenous Toxic Substances*

pH-gradient liposomes with acidic cores sequester lipophilic weak bases via the mechanism of ion trapping [22]. Peritoneal dialysis-medium-containing acidic core pH-gradient liposomes have been demonstrated to extract ionisable drugs and toxins in animal models. As early as 2012, a group investigated using drug-scavenging acidic-centre pH-gradient liposomes to treat calcium channel blocker (CCB) overdose [5]. Given the vascular and cardiac effects of drugs such as verapamil, these drugs are potentially life-threatening when ingested in an overdose. Current conventional decontamination methods are not reliably effective and efforts to establish a definitive antidote remain unsuccessful. Forster et al. initially showed that pH-gradient liposomes could sequester CCBs in vitro, before successfully demonstrating that IV injection of these liposomes into rats intoxicated with verapamil reversed the cardiovascular effects of intoxication. Although this study was an early step in showing the viability of liposome use in intoxication, issues of CARPA and low sequestration capacity relative to total toxic dose ingested remained. These limitations are mitigatable through introducing liposomes into dialysate, where liposomes are introduced to a compartment free from complement surveillance and intoxicant entrapped in liposomes can be removed from the body.

This same group developed LSPD using acidic-centre pH-gradient liposomes [7] in dialysis medium to increase dialytic clearance of target molecules using the lining of the abdominal cavity, the peritoneum, as the dialysis membrane. This group demonstrated the ability of liposomes in LSPD to sequester ionisable drugs via peritoneal dialysis in a rat model. Dialysate could then be extracted from the peritoneal cavity to eliminate the drug. The extraction of multiple drugs, including verapamil, propranolol, haloperidol and amitriptyline, was demonstrated. Of note, most of these drugs do not have specific antidotes and all are common presentations in overdose. LSPD removed 80 times more verapamil than in conventional dialysate controls. As in the previous study using IV administered liposomes, this method successfully demonstrated a reversal of the cardiovascular effects of verapamil in a rat model of verapamil overdose. The mechanism of entrapment was the same as for ammonia, with the lipophilic, weakly basic verapamil diffusing through the liposome membrane, then becoming protonated in the liposome centre and thus unable to exit through the liposome wall. This created a much larger "sump" for verapamil than regular dialysate, and therefore performed continuous extraction of verapamil from blood perfusing the peritoneal cavity. Of note, one of the further findings of this study was that smaller liposomes, 200 nm in diameter, had markedly greater systemic absorption from the peritoneal cavity than liposomes 800 nm in diameter.

Chapman et al. investigated whether the presence of acidic-centre liposomes in peritoneal dialysate could increase amitriptyline extraction via trans-liposomal pH gradient into dialysate in rats [23]. Based on estimates of peritoneal blood flow, the authors were the first to postulate that liposomes used in this way were effective in increasing the dialysis of protein-bound solutes in vivo. The same group have also investigated whether increasing blood concentrations of amitriptyline by adding either intravenous lipid emulsion (ILE) [23] or IV liposomes with the anionic phospholipid 1,2-dioleoyl-*sn*-glycero-3-phosphoglycerol (DOPG), which bind amitriptyline in the membrane, and would increase LSPD drug elimination [24]. These approaches represented an attempt at using liposomes or ILE to mitigate both of the major limitations to dialysis in intoxication—IV liposomes/emulsion to mitigate the problem of low relative blood concentrations, with intraperitoneal liposomes to increase dialysis of a bound solute. Although LSPD seems effective in increasing the removal of

protein-bound solute into dialysate, no effect from increasing blood concentrations using ILE or DOPG liposomes has been observed.
