title: Effect of octanol:water partition coefficients of organophosphorus compounds on biodistribution and percutaneous toxicity.
abstract: Knowledge of partition coefficient (log P) data can play a critical role in understanding the pharmacokinetic and pharmacodistributive properties of toxic organophosphorus (OP) compounds. Using a recently published gas chromatographic method, the octanol:water log P values for the compounds tabun (GA), sarin (GB), cyclosarin (GF), and O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX) were determined to be 0.384 +/- 0.033, 0.299 +/- 0.016, 1.038 +/- 0.055, and 0.675 +/- 0.070, respectively. Based on these data, the log P value of the fluorophosphonate fragment, common to GB, soman (GD), and GF, was determined to be -2.256 +/- 0.273. The predictive value for absorption and distribution of the determined log P values was compared to measured values. The time to onset of local fasciculations (47.3, 29.0, 8.8, 8.5, and 6.3 min, respectively) in guinea pigs exposed percutaneously to equilethal doses of GA, VX, GF, GB, or GD was used as an indicator of dermal penetration. There was a good correlation (r = 0.95) between the measured log P value and the rate of onset of local fasciculations. Assuming a direct correspondence, equilibrium tissue:blood log P may be estimated from octanol:water log P. Comparison of the estimated and directly measured tissue:blood log P revealed a correlation of 0.8 for GD in liver, muscle, and adipose tissue. Our results demonstrate the use of log P data to both predict absorption and determine the distribution of OP compounds in tissues. This facilitates further estimates of in vivo OP effects from in vitro experiments.
authors.affiliation: Laboratory Sciences Directorate, US Army Center for Health Promotion and Preventive Medicine, Aberdeen Proving Ground, MD 21010-5404, USA. steven.czerwinski@us.army.mil
authors.forename: Steven E
authors.initials: SE
authors.lastname: Czerwinski
authors.forename: John P
authors.initials: JP
authors.lastname: Skvorak
authors.forename: Donald M
authors.initials: DM
authors.lastname: Maxwell
authors.forename: David E
authors.initials: DE
authors.lastname: Lenz
authors.forename: Steven I
authors.initials: SI
authors.lastname: Baskin
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D002619:Chemical Warfare Agents / Q000493:pharmacokinetics / Q000633:toxicity; D006168:Guinea Pigs; D007928:Lethal Dose 50; D008297:Male; D000442:Octanols / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics / Q000633:toxicity; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D012869:Skin Absorption; D012995:Solubility; D014018:Tissue Distribution; D014867:Water / Q000737:chemistry*
chemical_list: D002619:Chemical Warfare Agents; D000442:Octanols; D009943:Organophosphorus Compounds; D014867:Water