Abstract
BackgroundIn Europe, synthetic corticosteroids are not allowed in animal breeding for growth-promoting purposes. Nevertheless, a high prevalence of non-compliant urine samples was recently reported for prednisolone, however, without any indication of unauthorized use. Within this context, 20β-dihydroprednisolone and the prednisolone/cortisol ratio have been suggested as potential tools to discriminate between exogenous and endogenous urinary prednisolone. In this study, the validity of these strategies was verified by investigating the plasma pharmacokinetic and urinary excretion profiles of relevant glucocorticoids in bovines, subjected to exogenous prednisolone treatment or tetracosactide hexaacetate administration to induce endogenous prednisolone formation. Bovine urine and plasma samples were analysed by liquid chromatography and mass spectrometry.ResultsBased on the plasma pharmacokinetics and urinary profiles, 20β-dihydroprednisolone was confirmed as the main prednisolone-derived metabolite, being detected in the biological fluids of all 12 bovines (plasma AUC0-inf of 121 h μg L−1 and urinary concentration > 0.695 μg L−1). However, this metabolite enclosed no potential as discriminative marker as no significant concentration differences were observed upon exogenous prednisolone treatment or tetracosactide hexaacetate administration under all experimental conditions. As a second marker tool, the prednisolone/cortisol ratios were assessed along the various treatments, taking into account that endogenous prednisolone formation involves the hypothalamic-pituitary-adrenal axis and is associated with an increased cortisol secretion. Significantly lower ratios were observed in case of endogenous prednisolone formation (i.e. ratios ranging from 0.00379 to 0.129) compared to the exogenous prednisolone treatment (i.e. ratios ranging from 0.0603 to 36.9). On the basis of these findings, a discriminative threshold of 0.260 was proposed, which allowed classification of urine samples according to prednisolone origin with a sensitivity of 94.2% and specificity of 99.0%.ConclusionThe prednisolone/cortisol ratio was affirmed as an expedient strategy to discriminate between endogenous and exogenous prednisolone in urine. Although the suggested threshold value was associated with high specificity and sensitivity, a large-scale study with varying experimental conditions is designated to optimize this value.
Highlights
In Europe, synthetic corticosteroids are not allowed in animal breeding for growth-promoting purposes
Repeatability and withinlaboratory reproducibility were evaluated based on the coefficients of variation (RSD) and were below the 15%tolerance level, specified in CD 2002/657/EC [22], except for 20α-dihydroprednisolone (22.3% at 0.5 μg L−1), which was considered acceptable because of the low target concentration
It is stated that 20β-dihydroprednisolone is no adequate marker metabolite as its discriminative potential will be strongly dependent on the time of sampling, relative to the triggering moment of endogenous prednisolone formation, whereby a small shift in time may already yield a completely different decision with respect to the origin of detected prednisolone
Summary
In Europe, synthetic corticosteroids are not allowed in animal breeding for growth-promoting purposes. A high prevalence of non-compliant urine samples was recently reported for prednisolone, without any indication of unauthorized use. Within this context, 20β-dihydroprednisolone and the prednisolone/cortisol ratio have been suggested as potential tools to discriminate between exogenous and endogenous urinary prednisolone. Synthetic glucocorticoids are extensively employed in cattle for therapeutic purposes because of their wellrecognized anti-inflammatory and immunosuppressive properties. Among these glucocorticoids, the most commonly used are dexamethasone methylprednisolone, and prednisolone. Appropriate withdrawal times have been defined for glucocorticoid treatment in order to comply with the maximum residue limits (MRLs), as they have been established for bovine edible tissues [6, 7]
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