Pharmacokinetics of the acetylcholinesterase oxime reactivator, HI‐6, in rhesus monkeys (Macaca mulatta): Effect of atropine, diazepam, and methoxyflurane anesthesia

Abstract

The pharmacokinetics of the bispyridinium oxime HI-6 (CAS reg. no. 34433-31-3; 1-(((4-aminocarbonyl)pyridinio)methoxy)methyl)-2-[hydroxy i mino)methyl)- pyridinium dichloride) was investigated in rhesus monkeys (Macaca mulatta). The effects of methoxyflurane anesthesia, administration of atropine with and without diazepam were determined on the serum half-life (t1/2), clearance rate (CL), and the volume of distribution (Vd) following intramuscular (IM) administration of HI-6 (30 mg kg-1). The control t1/2, CL and Vd of HI-offere 27 min, 8.6 ml min-1 kg-1 and 0.34 l kg-1, respectively. These parameters were unaffected by the co-administration of either atropine (0.5 mg kg-1, IM) or atropine and diazepam (0.5 mg kg-1, IM + 0.2 mg kg-1 IV, respectively). Methoxyflurane anesthesia resulted in a significant increase in the HI-6 t1/2 to 61 min concomitant with a decrease in the CL to 4.1 ml min-1 kg-1 with no change in the Vd. The increase in the t1/2 of HI-6 in methoxyflurane anesthetized monkeys is probably the result of a decrease in the clearance rate and, thus, excretion of HI-6 by the kidneys.

Plasma concentrations of pralidoxime methylsulphate in organophosphorus poisoned patients

“…This was interpreted as a decreased clearance with unaltered volume of distribution. Atropine and diazepam did not change pharmacokinetic parameters (Clement et al 1990).…”

Bioavailability and disposition kinetics of HI‐6 in Beagle dogs

“…Assuming rapid and complete absorption (F= 100%) of HI-6 (30 mg kg-1) from the intramuscular injection site, the pharmacokinetic parameters (mean f SD, n = 4) describing disposition of the drug in Rhesus monkeys (Macaca mulatta) were: half-life (27 f 5 min), clearance (8.6 _+ 1 -7 ml min-x kg) and apparent volume of distribution (0.34 f 0.1 1 kgl). 16 The administration of either atropine or atropine and diazepam caused no change in the pharmacokinetics of HI-6 in the monkeys. However, in monkeys maintained under methoxyflurane anaesthesia the mean half-life of HI-6 was increased from 27 to 61 rnin due to decreased systemic clearance of the drug, which probably could be attributed to reduced renal blood flow resulting from cardiovascular depression.…”

“…The apparent volume of distribution remained unchanged. 16 Based on a study performed in 22 healthy volunteer men to whom graded doses (62-5, 125,250, and 500mg) of HI-6 were administered by intramuscular injection, it was established that therapeutic plasma concentrations of the oxime, arbitrarily taken as 4 pg mll , were achieved by doses of 250 and 500 mg in about 5 rnin and maintained for 2 to 3 h.15 Very rapid absorption of the drug was supported by mean absorption half-lives of 6.9min (250mg dose) and 8 -4 rnin (500 mg dose). The apparent volumes of distribution were 0.39 1 kg-(250mg dose) and 0.361 kg-l (500mg dose) and total body clearances were 3.2mlmin-1xkg and 3-lrnlmin-lxkg for the 250 and 500mg doses, respectively.…”

Development and validation of a sensitive HPLC method for the quantification of HI-6 in guinea pig plasma and evaluated in domestic swine

“…Previous methods have been used to determine HI-6 plasma concentrations in mice [11], guinea pigs [17], rats [5,6,9], rabbits [10], canines [8,9], swine [7,16,18], non-human primates [17][18][19] and man [4].…”