TY - JOUR T1 - STUDIES ON THE TOXICITY AND PHARMACOLOGICAL ACTIONS OF <em>BIS</em>(DIMETHYLAMIDO) FLUOROPHOSPHATE (BFP) JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 231 LP - 245 VL - 112 IS - 2 AU - Arthur J. Okinaka AU - John Doull AU - Julius M. Coon AU - Kenneth P. DuBois Y1 - 1954/10/01 UR - http://jpet.aspetjournals.org/content/112/2/231.abstract N2 - Measurements of the acute toxicity of bis(dimethylamido) fluorophosphate (BFP) were conducted using several species of animals. The following approximate LD50 values in mgm./kgm. were obtained for BFP given intraperitoneally: rats 5, mice 1.4 and guinea pigs 2.5. When given intravenously to dogs the LD50 was between 5 and 10 mgm./kgm. After oral administration to rats the approximate LD50 was 7.5 mgm./kgm. indicating that the compound is well absorbed from the gastro-intestinal tract. No sex difference in susceptibility to the compound was noted in rats. The symptoms in all species were typical of those produced by cholinergic drugs. Symptoms referable to stimulation of the central nervous system were absent in dogs and less pronounced than the peripheral effects in all other species tested. The predominant cardiovascular effects of BFP in anesthetized dogs given doses in the range of the LD50 consisted of an initial transient pressor response with a slight increase in pulse rate. This was followed by a sharp, sustained fall in mean blood pressure, marked bradycardia and a wide pulse pressure. A gradual increase in the depressor effect of acetylcholine to a maximum increase of about 300-fold occurred during the first hour after intravenous administration of 1 mgm./kgm. of BFP to dogs. After lethal doses of BFP respiratory paralysis always preceded cardiac arrest. Measurements of the anticholinesterase action of BFP in vitro demonstrated that this compound produced 50 per cent inhibition of the cholinesterase activity of several tissues at a final molar concentration of 4 x 10-5M. After administration of ½ the LD50 dose to rats there occurred a gradual fall in the cholinesterase activity of serum, submaxillary gland, skeletal muscle and ileum over a period of 2 hours. Brain was only slightly affected suggesting that BFP does not readily gain access to the central nervous system. After single sublethal doses slow return of the enzyme activity to normal levels occurred over a period of several days. Daily administration of doses of 0.5 mgm./kgm. and higher doses of BFP to rats produced a cumulative toxic effect. The cumulative toxic action was accompanied by a progressive decrease in cholinesterase activity of brain and skeletal muscle with each succeeding dose of the drug. Submaxillary gland, cardiac muscle and serum exhibited a marked reduction in enzyme activity after the first dose of 0.1 mgm./kgm. or higher amounts of BFP and successive doses resulted in maintenance of the enzyme activity at a continued low level. Incubation of BFP with liver slices resulted in detoxification probably by hydrolysis of the fluorophosphate linkage. Measurement of the urinary excretion of BFP indicated that less than 2 per cent of the administered dose is excreted in the unchanged form. Premedication with atropine protected rats against two times the LD50 dose of BFP. Premedication with atropine and eserine increased the LD50 of BFP for mice 25 to 30-fold but provided no protection to rats. The results of this study indicated that BFP is a cholinergic compound with predominant effects on peripheral tissues. It produces essentially the same type of pharmacological effects as DFP and is of similar potency but BFP is stable in aqueous solutions and does not appreciably affect the central nervous system. It thus lacks the undesirable properties which have limited the clinical usefulness of DFP and therefore offers the possibility of being useful as a medicinal agent. ER -