Tissue Distribution of Loperamide and N-Desmethylloperamide Following a Fatal Overdose.pdf
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1、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 -opiate receptors in the intestine to reduce peristalsis. Loperamide la
2、cks the typical euphoric opiate effects when administered at recommended doses. Both loperamide and its major metabolite, N-desmethylloperamide, were isolated by liquidliquid extraction into n-butyl chloride from alkalinized samples. Extracts were analyzed by liquid chromatographyelectrospray-mass s
3、pectrometry 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-m particle diameter. The mobile phase consisted of 0.1% formic acid in deionized water (60%) and acetonitrile (40%) at
4、 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. B
5、ecause 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. Introduction Loperamide (Imodium), 4-(4-chlorophenyl)-4-hydroxy-N,N- d i m e t h y l -,-diphenyl-1-piperidi
6、ne butyramide hydrochlo- ride, is a piperidine opioid structurally related to diphenoxylate (Figure 1). Loperamide is administered orally for the manage- ment of both acute and chronic diarrhea through its reduction of gastrointestinal motility and, possibly, intestinal secretion (1,2). Loperamide w
7、as removed from Schedule V of the Con- trolled Substances Act in 1982 due in part to its efficacy and low abuse potential (3). Doses are available as 2-mg caplets, with or without 125 mg simethicone; cherry-mint-flavored liquids at 1 mg loperamide/5 mL; and mint-flavored chewable tablets also with s
8、imethicone. Also, until 1990, loperamide was sold in a drop formulation at a concentration of 2 mg/mL, but was withdrawn after reports of misuse in treating infant diarrhea (4). The pharmacokinetics of loperamide have been reviewed in detail (2,59) with reported peak plasma times of 45 h and elimina
9、tion half-lives between 7 and 19 h. As little as 0.3% of an administered dose of loperamide was present in plasma owing to first-pass metabolism (2). In addition to poor bioavail- a b i l i t y, loperamide does not penetrate the central nervous system well, and in recommended doses lacks the analges
10、ia typical of opioids. Single 4-mg oral doses resulted in peak plasma concentrations less than 0.001 mg/L for 3 individuals (10), and 6 individuals receiving 8-mg doses in either caplet or liquid form produced peak serum concentrations of 0.00224 and 0.00219 mg/L, respectively (6). N-Desmethyllopera
11、mide is a major inactive metabolite, and the primary route of lop- 750 Tissue Distribution of Loperamide and N-Desmethylloperamide Following a Fatal Overdose* Jason Sklerov1, Barry Levine1,2, Karla A. Moore2, Carol Allan2, and David Fowler2 1Division of Forensic Toxicology, Office of the Armed Force
12、s Medical Examiner, 1413 Research Blvd., Rockville, Maryland 20850 and 2Office of the Chief Medical Examiner, State of Maryland, 111 Penn St., Baltimore, Maryland 21201 Reproduction (photocopying) of editorial content of this journal is prohibited without publishers permission. Journal of Analytical
13、 Toxicology, Vol. 29, October 2005 Case Report * Disclaimer: The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Defense or of the Army, Navy, or Air Force. Author to whom corresponde
14、nce should be addressed: Office of the Chief Medical Examiner, 111 Penn St., Baltimore, MD 21201. Abstract Figure 1. Chemical structure of loperamide (A) and diphenoxylate (B). A B Journal of Analytical Toxicology, Vol. 29, October 2005 751 eramide excretion is as the unchanged drug in the feces. Lo
15、peramide has been implicated in numerous overdoses, particularly when administered to infants and children (1114). In a 5-year review of 8 poison control centers, 216 cases of lop- eramide ingestions were reported (15). The majority of the cases involved children under the age of 3 with the most com
16、mon symptoms including drowsiness, vomiting, abdom- inal pain, and nausea. Treatments have included gastric de- contamination and administration of naloxone. Loperamide therapy has also been contributory in cases of toxic mega- colon (16), pancreatitis (17), and lethal gastroenteritis (18). Methods
17、for the analysis of loperamide in biological samples have included radioimmunoassay (RIA) (5,10), liquid chro- matography (LC) (8,19), LCmass spectrometry (MS) (9), and LCMSMS (20,21). In this report, an LCMS method was devel- oped for the analysis of loperamide and N-desmethylloperamide in biologic
18、al specimens and applied to a postmortem case. Case History A 26-year-old Caucasian male with a medical history of schizophrenia, bipolar disorder, depression, and alcohol abuse was found unresponsive, face-down on the side of the road at approximately 0600 hours. Reportedly, the deceased was un- ab
19、le to sleep and went to a nearby convenience store to buy groceries at approximately 0300 hours that morning. When his roommate awoke, he found that the deceased had not returned and located him a short distance from their residence as de- scribed. His prescription medications at the time of his dea
20、th included lithium carbonate (300 mg), trazodone (100 mg), and aripiprazole (10 mg). Prescription dates and amounts of re- maining tablets were consistent with proper use. An empty blister pack of Equate loperamide (commercial name of U.S. generic drug line) was found with the body. The roommate st
21、ated the deceased “frequently” took the over- t h e - c o u n t e r anti-diarrheal medication for self-treatment of “stomach” prob- lems. At autopsy, the deceased was a well-nourished, well-devel- oped male, 5 feet, 10 in. in height, and weighing 183 pounds. Superficial abrasions were on the right s
22、ide of the forehead, the right infraorbital ridge, and the right side of the upper lip. There were no associated injuries to the facial skeleton, the skull, or brain. There was no other external evidence of injury and cut downs failed to identify trauma to the lower extremi- ties. The internal exami
23、nation was significant for a heart weight of 490 g associated with a left ventricular free wall and septal thickness of 1.5 cm and scattered 0.2-cm calcified nod- ules in the spleen. Regional lymph nodes were unremarkable. There were no gross abnormalities of the upper or lower gas- trointestinal tr
24、act. Microscopic examination identified left ven- tricular myocyte hypertrophy, non-specific reactive lobular hepatitis, moderate to focally severe chronic esophagitis, and fibrocalcified, non-caseating granulomatous inflammation of the spleen. Special stains for acid-fast bacilli and fungi were neg
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