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Oral reserpine administration in horses results in low plasma concentrations that alter platelet biology

Gilbertie, J. M., Davis, J. L., Davidson, G. S., McDonald, A. M., Schirmer, J. M., Schnabel, L. V.
Equine veterinary journal 2019 v.51 no.4 pp. 537-543
adhesion, adults, aspirin, blood platelets, half life, horses, industry, pharmacokinetics, reserpine, serotonin, tandem mass spectrometry
BACKGROUND: Reserpine is a popular drug in the equine industry for long‐term tranquilisation. Clinical observations revealed that blood from horses receiving oral reserpine was hypercoagulable. No studies have documented the pharmacokinetics of orally administered reserpine nor the effects of reserpine on platelets in horses. OBJECTIVES: To evaluate the pharmacokinetics of oral reserpine in horses and the effects of clinically relevant concentrations of reserpine on platelet functionality in vitro. STUDY DESIGN: Experimental controlled study. METHODS: The pharmacokinetics of oral reserpine (2.5 mg/horse, once) were determined in six healthy adult horses. Plasma samples were collected and concentrations of reserpine were determined by UPLC‐MS/MS. Using this data, the in vitro effects of reserpine on platelets were examined. Aggregation, adhesion and releasate assays for serotonin and thromboxane B₂ were performed on platelets exposed to varying concentrations of reserpine (0.01–10 ng/mL), aspirin (negative control) and saline (unexposed control). RESULTS: Oral reserpine administration demonstrated low plasma concentrations with a Cₘₐₓ of 0.2 ± 0.06 ng/mL and a prolonged half‐life of 23.6 ± 6.24 h. Simulations over a dose range of 2–8 μg/kg predicted Cₘₐₓ at steady state between 0.06–0.9 ng/mL. Platelets exposed to these reserpine concentrations in vitro displayed increased aggregation and adhesion compared to unexposed or aspirin‐exposed platelets as well as compared to higher concentrations of reserpine. These functional changes correlated with lower concentrations of serotonin and higher concentrations of thromboxane B₂ in the platelet suspension supernatant. MAIN LIMITATIONS: This study used a small number of horses and only in vitro platelet experiments. CONCLUSIONS: Oral reserpine demonstrates low plasma concentrations and a prolonged half‐life in horses. At these concentrations, reserpine causes significant changes in platelet function, most likely due to serotonin release and re‐uptake which primes platelets for activation and thromboxane B₂ release. These findings suggest that clinicians should harvest blood for biological processing prior to the onset of reserpine administration.