Pharmacokinetics of imipramine in narcoleptic horses

Objective-To validate use of high-performance liquid chromatography (HPLC) in determining imipramine concentrations in equine serum and to determine p harmacokinetics of imipramine in narcoleptic horses. Animals-5 horses with adult-onset narcolepsy. Procedure-Blood samples were collected before (time 0) and 3, 5, 10, 15, 20 , 30, and 45 minutes and 1, 2, 3, 4, 6, 8, 12, and 24 hours after IV admini stration of imipramine hydrochloride (2 or 4 mg/kg of body weight). Serum w as analyzed, using HPLC, to determine imipramine concentration. The serum c oncentration-versus-time curve for each horse was analyzed separately to es timate pharmacokinetic values. Results-Adverse effects (muscle fasciculations, tachycardia, hyperresponsiv eness to sound, and hemolysis) were detected in most horses when serum imip ramine concentrations were high, and these effects were most severe in hors es receiving 4 mg of imipramine/kg. Residual adverse effects were not appar ent. Value (mean +/- SD) for area under the curve was 3.9 +/- 0.7 h x mug/m l, whereas volume of distribution was 584 +/- 161.7 ml/kg, total body clear ance was 522 +/- 102 ml/kg/h, and mean residence time was 1.8 +/- 0.6 hours . One horse had signs of narcolepsy 6 and 12 hours after imipramine adminis tration; corresponding serum imipramine concentrations were less than the t herapeutic range. Conclusions and Clinical Relevance-Potentially serious adverse effects may be seen in horses administered doses of imipramine that exceed a dosage of 2 mg/kg. Total body clearance of imipramine in horses is slower than that i n humans; thus, the interval between subsequent doses should be longer in h orses.