Tissue Distribution of Loperamide and N-Desmethylloperamide Following a Fatal Overdose

Abstract

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.

Tolerance develops to the antiallodynic effects of the peripherally acting opioid loperamide hydrochloride in nerve-injured rats

“…However, the same tolerance-inducing protocol with loperamide did not induce a significant increase in spinal p-MOR-Ser 375 , suggesting that central MORs are not substrates for systemic loperamide tolerance. This notion is supported by pharmacokinetics of loperamide, which does not cross the blood-brain barrier in the dose range used in this study, and by numerous studies demonstrating the peripheral nature of loperamide actions [29,32,35]. Because the elimination half-life of loperamide (>2 hours) after subcutaneous injection is comparable to morphine (1.5 to 2 hours) [26], the lack of increased spinal p-MOR-Ser 375 by repeated dosing of loperamide is not due to limited drug exposure.…”

Assessment of a Candidate Marker Constituent Predictive of a Dietary Substance–Drug Interaction: Case Study with Grapefruit Juice and CYP3A4 Drug Substrates

“…The lack of effect on loperamide terminal t 1/2 was consistent with an interaction limited to the gut, which is typical of GFJ-drug interactions (Won et al, 2012;Bailey et al, 2013). In contrast to loperamide, the pharmacokinetics of the primary CYP3A4-mediated metabolite, N-desmethylloperamide, were unchanged in the presence of GFJ, which may reflect elimination rate-limited kinetics and/or more rapid distribution into peripheral tissues relative to loperamide (Sklerov et al, 2005). The pharmacokinetics of both loperamide and N-desmethylloperamide in the absence of GFJ were consistent with those reported at an equivalent (16 mg) (Mukwaya et al, 2005) or lower (2-4 mg) (Streel et al, 2005;Niemi et al, 2006) loperamide dose after dose normalization.…”

Loperamide as a Potential Drug of Abuse and Misuse: Fatal Overdoses at the Medical University of South Carolina

“…Therapeutic loperamide concentration in blood is cited at 0.24–3.1 ng/mL . According to the literature, fatal loperamide concentrations are reported as low as 63 ng/mL in a mixed drug toxicity fatality and as high as 1200 ng/mL . Nonfatal overdoses have been reported up to 130 ng/mL .…”