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Title: In vitro study of pharmacobezoar formation in simulated acetaminophen overdose.
Austin Authors: Li, Yu Kwan;Lam, Ka Fung;Wong, Cheung Lun William;Wong, Anselm Y 
Affiliation: Accident and Emergency Department, Princess Margaret Hospital, Hong Kong, Hong Kong SAR
Austin Toxicology Service, Austin Health, Heidelberg, Victoria, Australia
Department of Emergency Medicine, Austin Health, Heidelberg, Victoria, Australia
Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Australia
Victorian Poisons Information Centre, Austin Health, Heidelberg, Victoria, Australia
Department of Medicine and Radiology, Centre for Integrated Critical Care, Melbourne Medical School, University of Melbourne, Melbourne, Australia
Issue Date: Sep-2020
Date: 2019-12-26
Publication information: Clinical Toxicology 2020; 58(9): 900-906
Abstract: Objectives: There have been few studies of pharmacobezoar formation, but they can be an important contributor to overdose toxicity. Pharmacobezoars may explain the delayed peak or "double hump" pharmacokinetics, which were noted in previous case reports with delayed toxicity of acetaminophen (APAP). We validated the presence of APAP bezoar formation in a controlled modified in vitro environment simulating acute APAP overdose.Methods: This study involved the APAP and control groups (ferrous sulfate and chlorpheniramine). The APAP study group contained three subgroups of APAP with different dosage, i.e., 25 g (50 tabs)/37.5 g (75 tabs)/50 g (100 tabs). The positive control group containing ferrous sulfate, i.e., 15 g (50 tabs), has been reported previously to form pharmacobezoars in overdose. The negative control group containing chlorpheniramine, i.e., 200 mg (50 tabs), has not been reported to form pharmacobezoars in previous case studies. Tablets from each study group were placed into a separate pig stomach. Each stomach contained 28 ml USP standard simulated gastric acid. The stomach was placed in a plastic box filled with water maintaining at 37 °C. Each test group was examined for 4 h in the stomach. The primary outcome was the presence of clump formation. Positive clump formation was defined as tablets sticking together and the ability to maintain shape upon dissecting the pig stomach and lifting with fingers. Tablet clumps would then undergo dissolution testing with subsequent analysis of dissolution profiles.Results: Formation of tablets clumps was confirmed in APAP overdose in the in vitro environment. Clumps were noted to be present in the 37.5 g and 50 g APAP groups, while 25 g APAP was unlikely to form clumps. The dissolution profile of clump demonstrated slower release without reaching plateau at 60 min, as compared to corresponding individual tabs of APAP. f1 and f2 analyses showed the dissolution profile of clump was different compared to that of referenced individual tab.Conclusions: APAP clump formation was confirmed in acute overdose of 37.5 g or more. Dissolution tests revealed delayed and steady release of tablet residue from the clumps, which could explain prolonged or delayed toxicity in large APAP overdose.
DOI: 10.1080/15563650.2019.1705971
ORCID: 0000-0002-6817-7289
Journal: Clinical Toxicology
PubMed URL: 31875726
Type: Journal Article
Subjects: Acetaminophen
in vitro
massive overdose
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