Tissue distribution of loperamide and N-desmethylloperamide following a fatal overdose

We report a case involving a fatal intoxication with loperamide (Imodium). Loperamide is a synthetic opioid of the phenyl piperidine class used as an over-the-counter antidiarrheal. It exerts its effects through interaction with micro-opiate receptors in the intestine to reduce peristalsis. Loperamide lacks the typical euphoric opiate effects when administered at recommended doses. Both loperamide and its major metabolite, N-desmethylloperamide, were isolated by liquid-liquid extraction into n-butyl chloride from alkalinized samples. Extracts were analyzed by liquid chromatography-electrospray-mass spectrometry in selected-ion-monitoring mode. Rapid separation of the drug, metabolite, and internal standard (diphenoxylate) was achieved using a high-resolution C18 column with 1.8-microm particle diameter. The mobile phase consisted of 0.1% formic acid in deionized water (60%) and acetonitrile (40%) at a flow rate of 0.5 mL/min. Heart blood concentrations for loperamide and its metabolite were 1.2 mg/L and 3.3 mg/L, respectively. In contrast, reported peak plasma concentrations of loperamide after administration of recommended daily doses of 16 mg did not exceed 0.012 mg/L in controlled trials. Because the heart blood ethanol concentration was 0.08 g/dL, the medical examiner ruled that the cause of death was loperamide and ethanol intoxication, and the manner of death as undetermined.