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corticosteroid formulations in performance horses (Ferris et al. 2011). While the high lipid solubility of this formulation provides a prolonged local anti-inflammatory effect, it also leads to an increased residence time within the joint and a longer serum or plasma detection time, relative to more soluble compounds (Knych et al. 2014). Similar to previous reports (Autefage et al. 1986; Lillich et al. 1996; Soma et al. 2006; Menendez et al. 2012; Knych et al. 2014), in the current study, higher systemic concentrations were observed with increasing doses of MPA, including one horse receiving 600 mg which was 200 mg more than the next highest MPA cumulative dose (400 mg). However, in all studies, including the presently reported one, systemic concentrations fell below the regulatory threshold by 21 days post drug administration. In order to avoid inadvertent positive regulatory findings, it is prudent to be sensitive to previous corticosteroid administration. As was demonstrated in the current study, this is especially necessary in the case of previous MPA administration, as serum concentrations exceeded the regulatory threshold in a number of QHs previously treated with MPA. This is likely due to the longer residence time of this drug compared with other commonly used IA corticosteroids in horses. There are limited published reports describing the


clearance of isoflupredone following IA administration to horses (Lillich et al. 1996; Benson et al. 2014; Knych et al. 2015). In the study by Lillich et al. (1996), detectable concentrations of IP and IPA equivalents were reported for only 12 and 72 h, respectively following IA administration of 4 mg. More recent studies utilising more sensitive LC-MS/MS methods, reported that plasma isoflupredone concentrations fell below the regulatory threshold by 36 (Knych et al. 2015) and 72 h (Benson et al. 2014) post IA administration of 8 and 20 mg of IP, respectively. In the current study, regardless of the dose administered or the joint treated, serum IP concentrations fell below the ARCI regulatory threshold by the suggested withdrawal time guidance of 7 days. The results of previous studies as well as the presently reported one suggest that a 7 day withdrawal time guidance is adequate for IA administration of IPA at doses up to 30 mg. The most commonly used intra-articular betamethasone


product in horses is a combination betamethasone sodium phosphate/betamethasone acetate formulation. Current regulatory recommendations are based on an unpublished administration study whereby 20 horses received a single IA dose of 9 mg of betamethasone sodium phosphate/ betamethasone acetate (Anon 2014). The position statement reports plasma concentrations below the limit of quantitation (5 pg/ml) by 5 days post administration. Based on this, a regulatory recommendation of a 10 pg/ml threshold concentration with a corresponding 7 day withdrawal time was made. To the best of the authors’ knowledge, there is only one published report describing the pharmacokinetics of betamethasone following IA administration to horses (Menendez et al. 2015); however, the LOQ (50 pg/ml) in that study is well above the current regulatory threshold (10 pg/ ml) and therefore it is difficult to use this study in the assessment of the ARCI withdrawal time guidance. In the current study, the dose of betamethasone administered ranged from 6–60 mg. The majority of the horses studied had serum concentrations below 10 pg/ml by 7 days; however, 3 of the TB horses had levels above 10 pg/ml until 10 days post


administration (the next time point sampled). These 3 horses were at the upper end of the dose range (30 mg [one horse]; 60 mg [2 horses]) and interestingly all had received IA Polyglycan. It is not possible from the data in this study to make any inferences as to whether the prolonged detection is due to concurrent Polyglycan administration or simply high dose betamethasone administration, as a limited number of horses received this combination. However, until this potential interaction is more extensively studied, it may be prudent to observe an extended withdrawal time when administering high doses of betamethasone, whether in combination with Polyglycan or by itself. It is important to note that the ARCI recommended


withdrawal time guidance, as well as the results presented here apply only to IA corticosteroid administration and not administration by other routes. Other routes of administration, intramuscular in particular, necessitate a prolonged withdrawal time. As an example, Soma et al. (2011) have reported systemic concentrations of TCA above the regulatory threshold for upwards of 10 days, following i.m. administration of a 0.04 mg/kg dose. Higher doses and other non-IA routes of any of the corticosteroids studied here may require an even more prolonged withdrawal time to avoid inadvertent positive regulatory findings. Veterinarians should be aware that extravasation into subcutaneous tissues or inadvertent extra- articular injection during an intended IA injection may also necessitate a prolonged withdrawal time. Although serum elimination varied depending on the


dose and number of joints treated, based on the results of this study, maximum IA cumulative doses of 40 mg of TCA, 600 mg of MPA and 30 mg of IPA, either by themselves or in combination with other corticosteroids, should not result in positive regulatory findings if the ARCI withdrawal time guidance is followed for each drug. In the case of IA betamethasone administration, results of this study suggest that doses less than 30 mg should not result in excess of the regulatory threshold, when following the ARCI recommended withdrawal time guidance. However, based on the findings reported here, doses of 30 mg or greater may necessitate an extended withdrawal time as serum concentrations did not fall below the regulatory threshold until 10 days post administration. It should be noted that as the present study examined corticosteroid serum levels only and did not assess urine levels that extrapolating withdrawal time guidance in racing authorities where corticosteroids are regulated in urine may not be appropriate.


Authors’ declaration of interests No conflicts of interest have been declared.


Ethical animal research


Horses used in this study were under the care of private practitioners. Drugs were administered following a thorough examination and at the discretion of the treating practitioner.


Source of funding


Financial support for this study was provided by the Dolly Green Research Foundation, the California Horse Racing Board, Burnett Ranches, LLC and Equine Sports Medicine LRO Inc.


© 2016 EVJ Ltd


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