Bioavailability and disposition kinetics of HI‐6 in Beagle dogs

Abstract

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.

Pharmacokinetics of MMB4 DMS in Rats, Rabbits, and Dogs Following a Single IV Administration

“…12 These results were consistent with 46.5 + 7.8 minutes of elimination half-life and 221 + 41 mL/h/kg of clearance for HI-6 in dogs reported by another group of investigators. 13 The volume of distribution to central compartment for MMB4 in dogs (198 + 34 mL/kg) appeared to be comparable to that for HI-6 (125 + 54 mL/kg) 13 even though the average value for MMB4 was slightly larger than that for HI-6. These results also demonstrated species-related differences in HI-6 disposition kinetics, including the volume of distribution to the central compartment that was more conserved for MMB4 among different species.…”

“…Information on the pharmacokinetics of MMB4 is scant while the PK profiles of 2-PAM and HI-6 have been evaluated in various preclinical species. [9][10][11][12][13] To the best of our knowledge, there are no published results that describe the pharmacokinetics of MMB4 after intravenous (IV) administration. On the other hand, several investigators examined MMB4 PK profiles after intramuscular (IM) administration.…”

Pharmacology, Pharmacokinetics, and Tissue Disposition of Zwitterionic Hydroxyiminoacetamido Alkylamines as Reactivating Antidotes for Organophosphate Exposure

“…Several pharmacokinetic studies have been reported for 2-PAM and the more extended pyridinium structures such as MMB4 and HI-6 (Sidell and Groff, 1971;Baggot et al, 1993;Hong et al, 2013). Typically, small volumes of distribution (0.3-0.5 l/kg) and short half-lives (approximately 30 minutes) are evident.…”