Effect of lipid emulsion infusion on paliperidone pharmacokinetics in the acute overdose rat model: A potential emergency treatment for paliperidone intoxication

Abstract

Paliperidone prolongs cardiac repolarization in a concentration-dependent manner. Meanwhile, continuous infusion of intravenous lipid emulsion (ILE) has been established as a detoxification therapy for lipophilic drugs. However, this change in pharmacokinetics of various drugs following ILE administration remains to be clarified. Our objective is to clarify the effect of continuous infusion of ILE on the pharmacokinetics of overdosed paliperidone in rats. Paliperidone (20mg/kg) was administered orally to free-moving male Wistar rats. Continuous infusion (initial loading dose: 4ml/kg for 10min, followed by 4ml/kg/h for 12h) of ILE or acetated Ringer's solution (AR) was initiated 30min after paliperidone administration. Plasma concentration profile of paliperidone was monitored for 12h after administration. The plasma concentration and tissue/plasma concentration ratios of paliperidone were compared between ILE and AR groups. The rat group infused with ILE showed a higher area under the concentration–time curve (mean [S.D.]: 6102 [900.9] vs. 3407 [992.1]nghml−1, p=0.02) and longer elimination half-time (t1/2) (4.1 [0.9] vs. 2.2 [0.4]h, p=0.02) compared with the AR group. Tissue/plasma concentration ratios of paliperidone were lower in ILE rats than in AR rats (1.98 [0.70] vs. 3.82 [1.47] in the heart, p=0.04; 0.28 [0.29] vs. 1.27 [0.58] in the brain, p<0.001). In conclusion, continuous infusion of ILE would reduce tissue distribution and prolonged the t1/2 of paliperidone in rats. These results suggest that continuous infusion of ILE has potential as an emergency treatment for acute paliperidone intoxication.