title: Drug-drug interaction and doping, part 1: an in vitro study on the effect of non-prohibited drugs on the phase I metabolic profile of toremifene.
abstract: The present study was designed to provide preliminary information on the potential impact of metabolic drug-drug interaction on the effectiveness of doping control strategies currently followed by the anti-doping laboratories to detect the intake of banned agents. In vitro assays based on the use of human liver microsomes and recombinant CYP isoforms were designed and performed to characterize the phase I metabolic profile of the prohibited agent toremifene, selected as a prototype drug of the class of selective oestrogen receptor modulators, both in the absence and in the presence of medicaments (fluconazole, ketoconazole, itraconazole, miconazole, cimetidine, ranitidine, fluoxetine, paroxetine, nefazodone) not included in the World Anti-Doping Agency list of prohibited substances and methods and frequently administered to athletes. The results show that the in vitro model developed in this study was adequate to simulate the in vivo metabolism of toremifene, confirming the results obtained in previous studies. Furthermore, our data also show that ketoconazole, itraconazole, miconazole and nefazodone cause a marked modification in the production of the metabolic products (i.e. hydroxylated and carboxylated metabolites) normally selected by the anti-doping laboratories as target analytes to detect toremifene intake; moderate variations were registered in the presence of fluconazole, paroxetine and fluoxetine; while no significant modifications were measured in the presence of ranitidine and cimetidine. This evidence imposes that the potential effect of drug-drug interactions is duly taken into account in anti-doping analysis, also for a broader significance of the analytical results.
authors.affiliation: Laboratorio Antidoping, Federazione Medico Sportiva Italiana, Largo Giulio Onesti, 1, 00197, Rome, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Mazzarino
authors.forename: Xavier
authors.initials: X
authors.lastname: de la Torre
authors.forename: Ilaria
authors.initials: I
authors.lastname: Fiacco
authors.forename: Amelia
authors.initials: A
authors.lastname: Palermo
authors.forename: Francesco
authors.initials: F
authors.lastname: Botrè
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004300:Doping in Sports / Q000379:methods*; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D050216:Metabolic Detoxication, Phase I; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism / Q000493:pharmacokinetics; D015813:Substance Abuse Detection; D017312:Toremifene / Q000378:metabolism* / Q000493:pharmacokinetics*
chemical_list: D007527:Isoenzymes; D020845:Selective Estrogen Receptor Modulators; D017312:Toremifene; D003577:Cytochrome P-450 Enzyme System
keywords: H2 antagonists; anti-doping analysis; antidepressants; antifungal agents; drug-drug interaction; in vitro metabolism; masking strategy; toremifene