Loperamide toxicokinetics: serum concentrations in the overdose setting

To the Editor:

A web-based study published in 2013 suggested that loperamide was being abused to attenuate the symptoms of opioid withdrawal.¹ Marraffa et al recently reported a case series of patients who presented with cardiac conduction disturbances after loperamide abuse.² This case series outlined the clinical course of 5 patients, 3 of whom experienced life-threatening arrhythmias. Isolated serum levels were reported in four of these patients.

We report a subsequent hospitalization and pharmacokinetic profile of one of the patients in the case series.² A 30-year-old male presented to an outlying facility for a syncopal episode. The initial electrocardiogram (ECG) revealed a heart rate of 60 beats per minute, a QRS measurement of 192 ms, and a QT of 704 ms. He left against medical advice, only to be found pulseless and apneic by a family member hours later. He was brought back to the outlying facility and demonstrated multiple ventricular arrhythmias, including one episode of polymorphic ventricular tachycardia. He was transferred to our facility after being defibrillated multiple times. The patient reported that he had resumed his abuse of loperamide and had been taking two hundred 2-mg tablets daily for the last seven days. He has had at least four prior hospitalizations with a similar presentation associated with loperamide abuse. The patient's cardiac conduction disturbance was managed with a continuous infusion of isoproterenol. The conduction disturbance slowly resolved with a QRS of 96 ms and QTc of 489 ms on hospital day 9. He was discharged to an inpatient psychiatric facility on hospital day 13 with a QRS of 94 ms and a QT/QTc of 406/483 ms. Due to his prolonged toxicity we obtained serum loperamide concentrations at multiple time points to better understand his pharmaco- kinetic profile.

The reported pharmacokinetic half-life of loperamide is approximately 9–13 h, although longer half lives up to about 40.9 h have been reported with doses of 16 mg in healthy volunteer studies.^3–4 The toxicokinetics of loperamide have not been previously reported. The patient presented to our facility 20 h after his last reported 400-mg dose. On presentation his loperamide level was 120 ng/mL. His loperamide serum levels 32, 44, 57, and 70.5 h post-ingestion were 47 ng/mL, 30 ng/mL, 30 ng/mL, and 20 ng/mL, respectively (Figure 1). Published peak loperamide concentrations after doses of 2–16 mg were reported to be between 0.24 and 3.1 ng/mL and occurred 4–5.9 h after administration.^5–6 His first two serum concentrations demonstrated an initial decline consistent with the reported half-life based on population kinetics (8.9 h). However, subsequent serum concentrations demonstrated a half-life of approximately 34.8 h. Interpretation of this kinetic data is complicated by the patient's history of Crohn's disease, multiple small bowel resections, and ileostomy. Additionally, the patient did receive a single dose of buprenorphine 12 mg sublingually and amiodarone 150 mg intravenously 35 and 38 h after his reported ingestion, respectively. No other cytochrome P450 inhibitors or inducers were given during the time frame when serum concentrations were drawn. A comprehensive drug panel including synthetic cannabinoids and designer drugs conducted on urine by NMS Labs was negative.

Fig. 1. Serial serum loperamide concentrations in the overdose setting.

Our patient's ECG changes are consistent with previously published case reports.^2,7 The elimination half-life observed in our patient is not consistent with the reported half-life. Loperamide is a μ-receptor agonist, which may reduce gastrointestinal motility and result in delayed absorption of drug.⁸ Delayed absorption in the overdose setting may result in prolonged toxicity. Loperamide has also been reported to antagonize calcium channels, which may result in reduced gastrointestinal motility.⁹ The elimination kinetics of loperamide are not known in the overdose setting and a multi-compartment pharmacokinetic model cannot be excluded. Our patient also received medications that inhibit both cytochrome P450 3A4 and 2D6 enzymatic metabolism. These enzyme families are reported to play a role in the hepatic conversion of loperamide to the N-demethyl metabolite, and inhibition might have further slowed the elimination of parent drug.¹⁰ Genetic alterations in these enzymatic pathways could also alter the kinetics of loperamide, which may explain the wide range in half-lives reported in one pharmacokinetic study.³ It is unclear what, if any, impact the patient's altered gastrointestinal tract may have had on the kinetics of loperamide. Further kinetic studies are needed to assess the toxicokinetics of loperamide.

Declaration of interest

The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.