Caffeine‐induced hyperactivity in the horse: comparisons of drug and metabolite concentrations in blood and cerebrospinal fluid

Abstract

The goals of this study were to elucidate the temporal and quantitative relationships between caffeine and its major bioactive metabolites in blood and cerebrospinal fluid (CSF) and to characterize the pharmacokinetic-pharmacodynamic relationship for caffeine-induced changes in spontaneous locomotor activity in the horse. We hypothesized that caffeine and its metabolites distribute efficiently into the CSF to antagonize adenosine A1 and A2a receptors and that spontaneous locomotor activity correlates well with caffeine and/or metabolite concentrations in CSF and blood. A microdialysis system was developed to allow simultaneous monitoring of locomotor activity and collection of CSF and blood samples for pharmacokinetic analysis. CSF concentrations of caffeine and its metabolites were evaluated to determine the percentage of central adenosine receptor blockade by the established standard inhibition curves. Caffeine increased the spontaneous locomotor activity for up to 4 h in a dose-dependent manner. After 3 mg/kg caffeine administration, blood caffeine concentration as well as locomotor activity increased sharply to near peak level while CSF caffeine concentrations exhibited a slow rise to a steady-state 75 min later. High correlation coefficient was found between locomotor activity and caffeine concentrations in blood (R(2 )=0.95) and in CSF (R(2) = 0.93). At 3 mg/kg dosage, theophylline was the only detectable caffeine metabolite in the CSF. The concentrations reached in the CSF were sufficient to partially block central adenosine A1 (14% blockade) and A2a (11% blockade) receptors. There were no statistically significant differences between the pharmacokinetics of caffeine in the blood and CSF. This study provides novel evidence that locomotor stimulation in horses is closely correlated with caffeine concentrations in the blood and CSF and, furthermore, is consistent with blockade of central adenosine receptors.

Equine poisoning by coffee husk (Coffea arabicaL.)

“…Similar results were also observed by Vickroy et al [29], who reported an increase in motor activity in horses with plasma caffeine concentrations of 4,000 ng/ml. Therefore, the clinical signs observed in the horses participating in this study (compulsive walking, mydriasis, congested ocular mucosa and episcleral vessels and intense sweating) may reflect the high plasma concentrations of caffeine (51,564 ± 5,708 ng/ml) observed at T56.…”

“…The bioavailability of caffeine in horses after oral administration was 39% [ 28 ], and as the total average caffeine consumption by the animals in the present study was 78 mg per kilogram of body weight (mg/kg BW), therefore, on average, approximately 30 mg/kg BW of caffeine were absorbed by the animals over 56 h. Behavioral changes occur in horses when plasma caffeine concentrations are greater than 2,000 ng/ml [ 11 ]. Similar results were also observed by Vickroy et al [ 29 ], who reported an increase in motor activity in horses with plasma caffeine concentrations of 4,000 ng/ml. Therefore, the clinical signs observed in the horses participating in this study (compulsive walking, mydriasis, congested ocular mucosa and episcleral vessels and intense sweating) may reflect the high plasma concentrations of caffeine (51,564 ± 5,708 ng/ml) observed at T56.…”

Systematic analysis to assess the scientific validity of the international residue limits for caffeine and theophylline in horse‐racing

“…In vitro studies show that the minimal inhibitory concentration of cafeine at these receptors is about 1 µM (194 ng/ml). As reported by Vickroy et al, 24 the concentration of cafeine in the blood and the cerebrospinal luid highly correlates in horses and shows a concentration ratio of 0.87. In addition, they report a strong correlation between the efect of cafeine on the motor activity of horses and the concentration of cafeine in the cerebrospinal luid, which can be used as a reasonable indicator of the actual concentration of cafeine in the brain.…”

Equine lamellar energy metabolism studied using tissue microdialysis

“…In horses, microdialysis has been used in pharmacokinetic studies and for assessment of muscle energy metabolism (Chou et al, 2001;Edner et al, 2005Edner et al, , 2009Ingvastlarsson et al, 1992;Murchie et al, 2006;Vickroy et al, 2008). Lamellar microdialysis has been described for pharmacokinetic studies (Nourian et al, 2010a, b).…”