Pharmacokinetics and pharmacodynamics of methyl parathion.
Methyl parathion and other organophosphorus insecticides are widely used in agriculture. Poisonings to this class of compounds are common and exerted primarily through inhibition of acetylcholinesterase. Methyl parathion became a major health concern when it was illegally sprayed in private homes. Since there are limited data with which to predict the long-term effects resulting from a pattern of exposure to methyl parathion that may have occurred in domestic settings, studies were performed to compare its pharmacokinetics and pharmacodynamics after intravenous, oral or dermal exposure. Methyl parathion was given to adult female rats as a single dose intravenously (2.5 mg/kg) through a femoral catheter, orally (2.5 mg/kg) by gavage, or dermally (< or = 50 mg/kg) by application to shaved skin at the nape of the neck. Blood (200 microl) was collected at increasing times from a separate catheter or from the retro-orbital sinus. Cholinesterase activity was measured in blood and normalized to hemoglobin content, whereas activities in brain and peripheral tissues were normalized to protein. Blood methyl parathion was quantitated by gas chromatography-electron capture. The pharmacokinetics of methyl parathion after intravenous exposure best fit a model in which it was distributed between two compartments and rapidly eliminated. Maximal concentrations of methyl parathion ranged from 200 to 350 ng/ml. The half-life of methyl parathion was 51 minutes, its volume of distribution was 10.1 L/kg, and clearance was 108 ml/min/kg. The kinetics of methyl parathion after single oral exposure contrasted with those after intravenous exposure. Despite a high absorption coefficient, oral bioavailability of methyl parathion was less than 5%, and concentrations in blood were 2% or less of those after intravenous exposure. After single dermal exposure (25 or 50 mg/kg), blood methyl parathion levels increased during the first 6 h and then remained constant for the next 42 h at about 150 ng/ml. Despite differences in its pharmacokinetics, methyl parathion caused similar time-dependent changes in blood and brain cholinesterase activities after intravenous or oral administration. Maximal inhibition of blood cholinesterase occurred within 15-60 min, and activities recovered within 30 - 48 h. In contrast, inhibition of blood cholinesterase caused by single dermal exposure (> or = 25 mg/kg) to methyl parathion developed gradually over 24 h, but was sustained. Cholinesterase inhibited by a lower dose (< or = 12 mg/kg) of methyl parathion required up to 21 days to recover fully. The pharmacokinetics and pharmacodynamics of methyl parathion are complex, and the complexity varies with the route of exposure. A significant 'first pass' effect for methyl parathion is seen with oral administration. Dermal exposure to methyl parathion, as likely occurred with the illegal spraying of private homes and businesses, may exacerbate toxicity and increase the potential for long-term adverse health effects.
Kramer
Robert E
RE
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505, USA. rkramer@pharmacology.umsmed.edu
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Ing K
IK
D000818:Animals; D002802:Cholinesterases / Q000097:blood; D006801:Humans; D007306:Insecticides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008743:Methyl Parathion / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*
D007306:Insecticides; D008743:Methyl Parathion; D002802:Cholinesterases