Title page for ETD etd-03132006-113241

Document Type Master's Dissertation
Author Cordel, Claudia
Email fertility@tah.co.za
URN etd-03132006-113241
Document Title Pharmacokinetics and in vitro effects of imipramine hydrochloride on the vas deferens in cattle
Degree MMedVet (Gyn)
Department Production Animal Studies
Advisor Name Title
Prof H J Bertschinger
  • intravenous pharmacokinetics
  • domestic bull
  • imipramine hydrochloride
Date 2005-07-06
Availability unrestricted
This project was divided into two studies. The first investigated the pharmacokinetics of imipramine hydrochloride (IMI) in bulls. IMI was administered intravenously to three bulls (600-705.5 kg) at a dose of 2mg/kg body weight (BW). Intravenous plasma concentrations of IMI over time were determined by fluorescence polarization immunoassay (FPIA). IMI plasma concentration versus time profile was best described by a two compartmental open model with first-order rate constants. IMI distributed rapidly, (ta) at 7.2 4.2 min, exhibited a very large apparent steady state volume of distribution (Vdss) of 4.2 0.9 l/kg BW, had a very short terminal elimination half-life (tb) of 140 15 min and showed a rapid total body clearance (Cl) of 22.7 7 ml/min/kg. Both IMI and the pharmacologically active metabolite, desipramine was negligible in serum at 24 hours. All three bulls treated with IMI showed pronounced central nervous system signs immediately post injection. Signs of generalised weakness and ataxia were evident. All CNS signs dissipated 15-20 minutes post injection and should therefore not influence the treatment interval. An interval of at least 23 hours between repeat treatments of IMI, representing a period of at least 10 half-lives, is recommended. The dose of 2 mg/kg BW used in this study was similar to that routinely used in stallions without fatal side effects. One of the three bulls exhibited spontaneous emission and ejaculation with this dose.

The second study investigated the effects of IMI on ampullar strips of bulls in organ baths. Vasa deferentia were collected from 16 freshly slaughtered post-puberal bulls of various breeds. Longitudinal ampullar strips were prepared and placed into 20 ml modified Krebs bicarbonate solution, aerated with a mixture of 02 (95 %) and CO2 (5 %) in water-jacketed organ baths. The effect on the smooth muscle tissue of noradrenaline (NA) alone, NA in combination with IMI and IMI alone was evaluated. NA alone consistently produced dose-dependant smooth muscle tissue contractions. IMI doses equivalent to <1 mg/kg BW (body weight equivalent; bwe) had NA potentiating effects. Doses of <0.1 mg/kg bwe were consistently potentiating while doses of >0.1 mg to <1 mg/kg bwe partially blocked NA stimulating effects. Amplitude of rhythmic contractions increased while contraction frequency decreased at this level. This study supports the adrenergic potentiating effects of IMI at doses of 0.05-0.2 mg/kg bwe with higher doses having paradoxical effects. Doses of IMI < 2 mg/kg bwe completely blocked NA effects. Tissue response to NA, after IMI blockade, started to recover 146-186 minutes after application of IMI at <2 mg/kg bwe. In the absence of NA, IMI had no effect on smooth muscle activity. The time to an IMI effect on NA initiated smooth muscle activity was 8 minutes. On the basis of the results of this in vitro study, we propose that IMI can be used to enhance semen collection by means of electro-stimulation in domestic bulls and immobilised wildlife species such as buffalo, provided that the correct dose is used.

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