Pharmacokinetics and Pharmacodynamics of the Oxime HI6 in Dogs

The pharmacokinetics and pharmacodynamics of the oxime HI6 were investigated in conscious and anesthetized beagle dogs following intramuscular injection. The absorption of HI6 (100 mumol/kg) was slower in conscious dogs as compared to the anesthetized dogs, and the maximum concentrations in plasma were lower (200 instead of 300 mumol/l). In comparison, the elimination of HI6 (100 mumol/kg) was twice as rapid in the conscious dogs (ke = 0.013 instead of 0.006 min-1) as in the anesthetized animals and was equal to the elimination after injection of 50 mumol/kg (likewise in anesthesia). The more rapid elimination was accompanied by a greater renal excretion of unchanged HI6 (60% instead of 40% in 3 h). HI6 penetrated the blood-brain barrier. The concentration of the oxime in CSF increased rapidly during the absorption phase (by 30 min after injection). The maximum concentrations (1-3 mumol/l) were reached between 60 and 120 min. The peak concentrations in plasma and CSF did not correlate with each other. In the anesthetized dogs the higher dose of HI6 (100 mumol/kg) caused a steady decrease in mean blood pressure (20 mm Hg) and blood flow (50%) in the femoral artery and a fall in left ventricular pressure (20 mm Hg), lasting for at least 60 min; the lower dose (50 mumol/kg) did not cause circulatory effects. EKG, respiration, hematocrit, arterial blood gases, and pH were not influenced.