Elimination profiles of betamethasone after different administration routes: Evaluation of the reporting level and washout periods to ensure safe therapeutic administrations

Abstract

Betamethasone (BET) is prohibited in sports competitions when administered by systemic routes, and it is allowed by other routes for therapeutic purposes. In out‐of‐competition periods, there is no restriction of use. The present work aimed to assess the urinary excretion of BET and its metabolites after allowed and prohibited administrations to verify the suitability of the current reporting level of 30 ng/ml used to distinguish allowed and prohibited administrations and to establish washout periods for oral and intramuscular (IM) administrations when out‐of‐competition treatments are needed. BET was administered to healthy volunteers by different routes: topical (10 mg/day for 5 days, n = 6 males), intranasal (320 μg/day for 3 days, n = 4 males and 4 females), oral (0.5 mg, n = 8 males) or IM (6 mg, n = 6 males, or 12 mg, n = 4 males and 4 females). Urine and plasma samples collected before and after administration were analysed using liquid chromatography–tandem mass spectrometry. Among all studied metabolites, the parent drug was selected as the best discriminatory marker. After topical administration, BET concentrations were lower than 6.6 ng/ml. However, after intranasal treatment, some samples at concentrations close to or higher than 30 ng/ml were detected, suggesting the need to revise the current reporting level. Urinary concentrations after oral and intranasal administrations were similar, and after IM administration, concentrations were much higher. Taking into account all information, a urinary reporting level of 60 ng/ml is proposed. Washout periods of at least 48 and 96 h are recommended after oral and IM administrations, respectively.

Elimination profiles of prednisone and prednisolone after different administration routes: Evaluation of the reporting level and washout periods to ensure safe therapeutic administrations

“…In the present work, dermatological administration of PRED at multiple doses was studied, and relatively high concentrations were obtained for PRED, PSONE, and 20β‐dihydro‐PRED (maximum concentrations detected in urine of 12, 18, and 25 ng/ml, respectively) compared with concentrations obtained for other GCs using the same administration route 12,14,22 …”

“…In addition to the parent drugs, the most important metabolites (20‐dihydro metabolites) 20,25 were included. 6βOH‐PRED was also included because the 6β‐hydroxy metabolites have been reported to be important for other GCs 13,14,17,18,21,22 . A summary of the validation results is presented in Table 3.…”

“…Moreover, previous studies have demonstrated that discriminatory criteria should be compound specific. Whereas for budesonide a metabolite, 6β‐hydroxybudesonide, was found to be the best marker to discriminate between allowed and prohibited administrations, 13,21 the parent drug was demonstrated to be the best discriminatory marker to detect the misuse of triamcinolone acetonide 14,18 and betamethasone 22 . Therefore, the most adequate marker and the reporting level should be defined for each GC.…”

“…On the other hand, because GCs are allowed for therapeutic purposes in out‐of‐competition periods without restrictions, there is a need of evaluating the elimination times in urine in order to define washout periods to avoid AAF when athletes undergo a systemic treatment in an out‐of‐competition period close to competition. Recent studies have shown relatively high concentrations of triamcinolone acetonide in urine for 15–23 days after IM administration 14,18 ; however, elevated concentrations of betamethasone are detected up to Day 6 after IM administration 22 . Therefore, the washout periods should also be evaluated for each specific GC.…”

A novel approach to improve detection of glucocorticoid doping in sport with new guidance for physicians prescribing for athletes

“…The initial results were corroborated and expanded on by numerous studies published thereafter which further evidenced the systemic distribution by measuring not only urinary but also plasma concentrations of the drugs. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] As a consequence, the status of local injections in the WADA Prohibited List needed to be re-evaluated. 5-7 13 19 20 The need for reliable and practical guidance for physicians treating athletes with GCs has also been recognised by WADA since the first inclusion of GCs on the Prohibited List.…”