Morphine/Codeine Ratio, a Key in Investigating a Case of Doping

Today's doping tests involve longitudinal monitoring of urinary steroids including the testosterone glucuronide and epitestosterone glucuronide ratio (T/E) in an Athlete Biological Passport (ABP). The aim of this study was to investigate the possible influence of short-term use of codeine on the urinary excretion of androgen metabolites included in the steroidal module of the passport prior to and after the co-administration with testosterone. The study was designed as an open study with the subjects being their own control. Fifteen healthy male volunteers received therapeutic doses of codeine (Kodein Meda) for 6 days. On Day 3, 500 mg or 125 mg of testosterone enanthate (Testoviron®-Depot) was administered. Spot urine samples were collected for 17 days, and blood samples were collected at baseline, 3, 6, and 14 days after codeine intake. The circulatory concentration of total testosterone decreased significantly by 20% after 3 days' use of codeine (p = 0.0002) and an atypical ABP result was noted in one of the subjects. On the other hand, the concomitant use of codeine and testosterone did not affect the elevated urinary T/E ratio. In 75% of the individuals, the concentration of urinary morphine (a metabolite of codeine) was above the decision limit for morphine. One of the participants displayed a morphine/codeine ratio of 1.7 after codeine treatment, indicative of morphine abuse. In conclusion, our study shows that codeine interferes with the endogenous testosterone concentration. As a result, the urinary steroid profile may lead to atypical findings in the doping test.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Codeine influences the serum and urinary profile of endogenous androgens but does not interact with the excretion rate of administered testosterone

Lehtihet

Andersson

Börjesson

et al. 2017

“…Nevertheless, since these compounds constitute a class of prohibited substances of the WADA Prohibited List, test methods enabling the qualitative and, in case of morphine, quantitative determination of relevant analytes are required . Narcotics are banned in‐competition only, and while urine analyses readily allow for the unequivocal identification of compounds classified by WADA within the category of narcotics, challenges similar to stimulants exist, for example concerning the retrospective accuracy, but also regarding identifying AAFs caused by the use/consumption of permitted drugs and produce . Hence, the utility of complementary approaches utilizing alternative matrices was assessed, and by means of fully automated DBS desorption/online‐SPE/LC‐MS/MS the possibility to sensitively analyze morphine, codeine, oxycodone, hydrocodone, and fentanyl was demonstrated .…”

Section: Narcotics and Glucocorticoidsmentioning

confidence: 99%

“…[138] Narcotics are banned in-competition only, and while urine analyses readily allow for the unequivocal identification of compounds classified by WADA within the category of narcotics, challenges similar to stimulants exist, for example concerning the retrospective accuracy, [25] but also regarding identifying AAFs caused by the use/consumption of permitted drugs and produce. [145] Hence, the utility of complementary approaches utilizing alternative matrices was assessed, and by means of fully automated DBS desorption/online-SPE/LC-MS/MS the possibility to sensitively analyze morphine, codeine, oxycodone, hydrocodone, and fentanyl was demonstrated. [146] Supported by stable isotopelabelled ISTDs corresponding to all five target analytes, online SPE was performed using a C18 RP stationary phase.…”

Section: Stimulantsmentioning

confidence: 99%

Annual banned‐substance review: analytical approaches in human sports drug testing

Thevis

Kuuranne

Geyer

et al. 2017

There has been an immense amount of visibility of doping issues on the international stage over the past 12 months with the complexity of doping controls reiterated on various occasions. Hence, analytical test methods continuously being updated, expanded, and improved to provide specific, sensitive, and comprehensive test results in line with the World Anti-Doping Agency's (WADA) 2016 Prohibited List represent one of several critical cornerstones of doping controls. This enterprise necessitates expediting the (combined) exploitation of newly generated information on novel and/or superior target analytes for sports drug testing assays, drug elimination profiles, alternative test matrices, and recent advances in instrumental developments. This paper is a continuation of the series of annual banned-substance reviews appraising the literature published between October 2015 and September 2016 concerning human sports drug testing in the context of WADA's 2016 Prohibited List. Copyright © 2016 John Wiley & Sons, Ltd.

“…This leads to the formation of 2 metabolites, with pronounced differences in terms of biological activity, clearance, and toxicity: morphine-3-glucuronide (M3G, 50%-65%) and morphine-6-glucuronide (M6G, 5%-10%). [24][25][26][27][28][29][30][31][32][33][34][35][36] Analytical (eg, enzymatic hydrolysis), [37][38][39][40][41] physiological (eg, genetic polymorphism) 42 or non-physiological (eg, drug-drug interaction) factors [43][44][45][46][47][48][49] were reported to interfere with morphine determination in urine. Concerning, specifically, drug-drug interaction, experimental evidence indicates the ability of several agents (eg, antidepressants, antifungals) to significantly alter the activity of the enzymes involved in the principal metabolic pathways of morphine, with a consequent increase of its plasma concentration and decrease of the urinary levels of its metabolites.…”

mentioning

confidence: 99%

Effect of non‐prohibited drugs on the phase II metabolic profile of morphine. An in vitro investigation for doping control purposes

Ambrosio

Torre

Mazzarino

et al. 2018

The potential consequences of drug-drug interaction on the strategies adopted by anti-doping laboratories to report an adverse analytical finding for morphine were investigated. We evaluated in vitro the effects of 14 drugs on the principal metabolic pathways of morphine. The selected drugs are among those most commonly used by the athletes, none of them presently included in the World Anti-Doping Agency (WADA) Prohibited List. The non-prohibited drugs included 4 antifungals (fluconazole, itraconazole, ketoconazole, and miconazole), 6 benzodiazepines (alprazolam, bromazepam, clonazepam, lorazepam, lormetazepam, and triazolam), and 4 non-steroidal anti-inflammatory drugs (diclofenac, ibuprofen, ketoprofen, and nimesulide). The in vitro assays were based on the use of either human liver microsomes or uridine 5'-diphospho-glucuronosyl-transferases. Morphine and its glucuronides were determined by developed liquid chromatography-mass spectrometry procedure after dilution with an aqueous solution containing their deuterated isotopologues as internal standards. Morphine is mainly excreted as phase II metabolites: about 70% of the parent compound is found to be biotransformed by UGT2B7 to morphine-3-glucuronide (6065%) and morphine-6-glucuronide (5-10%). A reduction of the enzymatic activity of the UGT2B7 was recorded in the presence of 9 of the 14 drugs under investigation (ketoconazole, miconazole, itraconazole, diclofenac, ibuprofen, clonazepam, lorazepam, lormetazepam, and triazolam), with a consequent significant reduction of the levels of the glucuronide metabolites. This phenomenon in vivo may affect the rate of the urinary excretion of morphine with the risk of reporting "false negative" results, especially in case of results close to the decision limit value set by WADA.