Pharmacokinetics of dextromethorphan and its metabolites in horses following a single oral administration. Issue 6 (3rd October 2016)

• Record Type: Journal Article
• Authors: Corado, Carley R.; McKemie, Daniel S.; Knych, Heather K.
• Is Part Of: Drug testing and analysis. Volume 9:Issue 6(2017)
• Page Start: 880
• Page End: 887
• Publication Date: 2016-10-03
• Subjects: dextromethorphan -- horse -- racehorse -- metabolism -- pharmacokinetics -- dextrorphan; Drugs -- Analysis -- Periodicals; Drug testing -- Periodicals; Chemistry, Forensic -- Periodicals; 615.1901
• DOI: 10.1002/dta.2060
• Languages: English
• ISSNs: 1942-7603

Abstract

Abstract : Dextromethorphan is an N‐methyl‐D‐aspartate (NMDA) non‐competitive antagonist commonly used in human medicine as an antitussive. Dextromethorphan is metabolized in humans by cytochrome P450 2D6 into dextrorphan, which is reported to be more potent than the parent compound. The goal of this study is to describe the metabolism of and determine the pharmacokinetics of dextromethorphan and its major metabolites following oral administration to horses. A total of 23 horses received a single oral dose of 2 mg/kg. Blood samples were collected at time 0 and at various times up to 96 h post drug administration. Urine samples were collected from 12 horses up to 120 h post administration. Plasma and urine samples were analyzed using liquid chromatography‐mass spectrometry, and the resulting data analyzed using non‐compartmental analysis. The Cmax, Tmax, and the t1/2 of dextromethorphan were 519.4 ng/mL, 0.55 h, and 12.4 h respectively. The area under the curve of dextromethorphan, free dextrorphan, and conjugated dextrorphan were 563.8, 2.19, and 6, 691 h*ng/mL respectively. In addition to free and glucuronidated dextrorphan, several additional glucuronide metabolites were identified in plasma, including hydroxyl‐desmethyl dextrorphan, desmethyl dextrorphan, and three forms of hydroxylated dextrorphan. Dextromethorphan was found to be eliminated from the urine predominately as the O‐demethylated metabolite, dextrorphan. Several additional metabolites including several novel hydroxy‐dextrorphan metabolites were also detected in the urine in both free and glucuronidated forms. No significant undesirable behavioural effects were noted throughout the duration of the study. Copyright © 2016 John Wiley & Sons, Ltd. Abstract : Dextromethorphan is an ARCI class 4 prohibited substance in horse racing. Following oral administration of dextromethorphan to 23 horses (7 sedentary and 16 exercised), drug concentrations were still above the LOD of the assay at 96 h with the glucuronidated form of the major metabolite still detected at 96 h post administration. Several additional metabolites were also identified in both blood and urine including one not previously reported in any species.