Bioavailability and disposition kinetics of HI-6 in Beagle dogs

The absorption and disposition kinetics of HI-6 were determined in Beagle dogs given single doses (25 mg kg-1) of the drug by the intravenous, intramuscular, and oral routes. Concentrations of the oxime in plasma and urine were measured by HPLC. A two-compartment open model was used to describe the disposition curve following intravenous drug administration while a one-compartment open model with first-order absorption adequately described the data following intramuscular or oral administration of the dose. Extravascular distribution of HI-6 was limited (Vss 203 ml kg-1) and the drug was eliminated rapidly after intravenous administration (t1/2 46.5 min, MAT 55.4 min). Systemic clearance was 3.68 ml min-1 x kg. A major fraction of the dose (63.7 per cent) was excreted in urine over a 24-h collection period. Following intramuscular drug administration, the absorption half-life (t1/2(a), 5.3 min), MAT (17.1 min), Cmax (70.37 micrograms ml-1) and tmax (15.9 min) indicate that the drug was rapidly absorbed. Systemic availability was 83.43 per cent after oral drug administration, absorption was preceded by a lag time (23.2 min). The t1/2(a) (41.5 min), MAT (81.6 min), Cmax (4.30 micrograms ml-1) and Tmax (90.6 min) indicate somewhat delayed absorption. Systemic availability (11.38 per cent) and the fraction of dose excreted unchanged in the urine (9.3 per cent) show that the drug was poorly absorbed. The apparent half-life (58.0 min) and MRT (137.6 min) following oral administration were significantly longer (p < 0.05) than following intravenous or intramuscular administration suggesting that the rate of absorption from the gastrointestinal tract decreases the elimination rate of the drug. In conclusion, HI-6 has limited distribution within the body, is rapidly eliminated mainly by renal excretion unchanged in the urine, and the bioavailability (i.e. rate and extent of absorption) of the drug varies with the route of administration.