Pharmacokinetics of propetamphos following intravenous administration in the F344 rat.

Propetamphos [(E)-1-methylethyl 3-[[(ethylamino)methoxyphosphinothioyl]oxy]-2-butenoate], the active ingredient in Safrotin, is an organophosphate developed by Sandoz, Ltd. (Switzerland) as an insecticide (1). Although metabolism of propetamphos has been previously investigated (2,3), there is no pharmacokinetic data available in the literature. The current studies were undertaken to investigate the pharmacokinetics of propetamphos following intravenous administration in male and female Fischer 344 (F344) rats. Rats were dosed via an indwelling jugular cannula at a dose of 12 mg/kg (one-tenth the oral LD-50). Blood samples were withdrawn via the cannula at predetermined timepoints to quantitate plasma concentrations of propetamphos over time. Propetamphos is highly bound to plasma proteins (free fraction = 0.06). Free propetamphos concentration in plasma vs. time data were analyzed by noncompartmental methods. The terminal elimination rate constant, lambda, was significantly different for males versus females (0.015 min-1 for males and 0.037 min-1 for females, p = 0.001). Plasma was cleared of unbound propetamphos at rates of 0.559 +/- 0.069 and 0.828 +/- 0.181 L/min/kg for males and females (mean +/- standard error). Mean residence times (MRTs) for propetamphos in the body for males and females were 28.3 +/- 5.7 and 14.4 +/- 3.5 min, and the volume of distribution at steady state (Vss) was 14.7 +/- 2.6 and 12.3 +/- 4.5 L/kg. The differences in these parameters, clearance (CI), MRT, and Vss, were not statistically significant at the p < 0.05 level for males versus females, but MRT was nearly significantly different (p = 0.08).(ABSTRACT TRUNCATED AT 250 WORDS)