In vitro investigation on the effect of antifungals, benzodiazepines and non-steroidal anti-inflammatory drugs on the metabolic profile of morphine

Morphine belongs to the class of narcotic analgesics and is the largest and most active alkaloid of opium. It interacts with opioid receptors and is an agonist at the μ receptor and for these properties it is widely used in pain treatment. Morphine is extensively metabolized by the liver via conjugation with glucuronic acid, process catalyzed by uridine diphosphate glucuronosyltransferase (UDPGT). The conjugation with glucuronic acid occurs both on hydroxyl group in position 3 and 6, leading to the formation of morphine-3-glucuronide and morphine-6-glucuronide respectively. In human doping control, the World Anti-Doping Agency (WADA) has banned the use of morphine only in competition and set a threshold value of 1000 ng/mL. Both physiological (i.e. age, sex, genetic polymorphism) and non-physiological factors (i.e. drug-drug interactions, pathological status) might alter the pharmacokinetics of morphine, and therefore its urinary levels leading to an incorrect interpretation of the analytical results. Among those non-physiological factors a very important role is represented by drug-drug interactions (metabolic inhibition or induction). Little information is available regarding the relevance of this phenomenon in doping control field.