Pharmacokinetics of hydroxyzine and cetirizine following oral administration of hydroxyzine to exercised Thoroughbred horses

Abstract

Hydroxyzine is a first‐generation antihistamine and cetirizine, a second‐generation antihistamine and active metabolite of hydroxyzine. Hydroxyzine is commonly used in performance horses and as such its use in closely regulated; however, there are no published studies suitable for establishing appropriate regulatory recommendations. In the current study, 12 exercised Thoroughbred research horses received a single oral administration of 500 mg of hydroxyzine. Blood and urine samples were collected prior to and up to 96 hr postdrug administration and concentrations of hydroxyzine and cetirizine determined using liquid chromatography‐tandem mass spectrometry. A joint parent/metabolite population 2‐compartment pharmacokinetic model with first‐order absorption and elimination was utilized to describe the pharmacokinetics of both compounds. Serum hydroxyzine and cetirizine concentrations were above the limit of quantitation (0.1 ng/ml) of the assay at 96 hr (the last time point sampled). The terminal half‐life was 7.41 and 7.13 hr for hydroxyzine and cetirizine, respectively. Findings from this study suggest that a prolonged withdrawal time should be observed if this compound is used in performance administered to performance horses and is classified as prohibited substance by the applicable regulatory body.

Plasma and urine pharmacokinetics of hydroxyzine and cetirizine following repeated oral administrations to exercised horses

“…The continuous covariate for body weight was not significant for any of the parameters, which was probably due to the narrow body weight range for the study. The estimated hydroxyzine oral plasma clearance from the herein repeated dose study is 10.1 ml/min/kg which is slightly less than the serum value obtained from the Knych et al., 2019 single‐dose study (13.4 ml/min/kg). On the contrary, the estimated cetirizine oral plasma clearance from the herein study (20 ml/min/kg) is larger than both the Olsén et al., 2008 (8.2 ml/min/kg) and Knych et al., 2016 (9.2 ml/min/kg serum) repeated dose cetirizine studies.…”

“…Examination of the plasma PK profiles from the single oral dose hydroxyzine Knych et al., 2019 study shows that all 12 horses have serum concentrations below a possible plasma hydroxyzine SL (0.5 ng/ml) by the proposed DT of 96 h. Application of the Toutain approach to the 2007 and 2016 cetirizine oral studies affords EPC values of 68 and 60 ng/ml, respectively. This corresponds to cetirizine IPC values of 0.14 and 0.12 ng/ml which are comparable but slightly less than a possible plasma SL for cetirizine of 0.3 ng/ml as a marker of hydroxyzine administration.…”

“…Recently, Knych et al. (2019) have described the PK of hydroxyzine and cetirizine as metabolite from single‐dose administration of hydroxyzine to 12 horses in serum and to a limited extent in urine. The plasma/serum PK of cetirizine after repeated oral administration to horse has been previously described by Olsén et al.…”

Pharmacokinetics of diphenhydramine following single‐dose intravenous and oral administration in non‐fasted adult horses

“…H1 antagonists interact with histamine receptors located on cells within various tissues (vascular endothelium, bronchial smooth muscle, and peripheral nerve endings) to stop histamine binding and therefore prevent histamine's pro‐inflammatory effects (Leurs et al, 2002) that lead to clinical signs. While various H1 antagonists are commonly used in horses, including hydroxyzine, diphenhydramine, and cetirizine, knowledge of their pharmacokinetics and pharmacodynamics is gradually being elucidated (Knych et al, 2016, 2019; Olsén et al, 2007, 2008, 2011). Pharmacokinetics of intravenously administered diphenhydramine have been evaluated in adult horses in one study (Wasfi et al, 2003); however, this is not a feasible route of administration for long‐term use or by laypersons.…”

“…diphenhydramine, and cetirizine, knowledge of their pharmacokinetics and pharmacodynamics is gradually being elucidated (Knych et al, 2016(Knych et al, , 2019Olsén et al, 2007Olsén et al, , 2008Olsén et al, , 2011. Pharmacokinetics of intravenously administered diphenhydramine have been evaluated in adult horses in one study (Wasfi et al, 2003); however, this is not a feasible route of administration for long-term use or by laypersons.…”