Larvae of Chironomus riparius were used to demonstrate a statistically significant relationship between four variables: parathion concentration in water (nominally 20 to 500 μg/L), duration of exposure, symptoms of toxicity, and in vivo cholinesterase (ChE) inhibition. The symptoms of toxicity were a series of swimming behaviors that were categorized and assigned numerical values according to intensity of poisoning. These values were correlated with ChE inhibition by a polynomial regression. Therefore, symptoms of poisoning could be mathematically estimated from measurements of percent ChE inhibition. A three‐dimensional relationship between ChE inhibition, the logarithm of exposure time, and the logarithm of parathion concentration was established. This permits the characterization of the range of conditions for the onset of a given toxicity symptom and also predicts the symptom for which values for at least two of these variables are provided.

Larvae of Chironomus riparius were used to demonstrate a statistically significant relationship between four variables: parathion concentration in water (nominally 20 to 500 pg/L), duration of exposure, symptoms of toxicity, and in vivo cholinesterase (ChE) inhibition. The symptoms of toxicity were a series of swimming behaviors that were categorized and assigned numerical values according to intensity of poisoning. These values were correlated with ChE inhibition by a polynomial regression. Therefore, symptoms of poisoning could be mathematically estimated from measurements of percent ChE inhibition. A three-dimensional relationship between ChE inhibition, the logarithm of exposure time, and the logarithm of parathion concentration was established. This permits the characterization of the range of conditions for the onset of a given toxicity symptom and also predicts the symptom for which values for at least two of these variables are provided.

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Two metabolites of the tranquilizer azaperone were extracted from alkalinized horse urine after treatment with beta-glucuronidase/sulfatase from limpets (Patella vulgata). The metabolites were identified by a combination of independent chemical synthesis and GC/MS and 1H NMR analysis. The metabolites were identified as 1-(fluorophenyl)-4-[4-(5-hydroxy-2-pyridinyl)-1-piperazinyl]-1-butanol, designated as 5'-hydroxy-azaperol, and 1-(fluorophenyl)-4-[4-(5-hydroxy-2-pyridinyl)-1-piperazinyl]-1-butanone, designated as 5'-hydroxyazaperone. A TLC screening test was developed for detecting both metabolites in basic extracts of horse urine treated with beta-glucuronidase/sulfatase. The screening test was used to detect azaperone metabolites in extracts of horse urine collected for 24 h after intravenous administration of azaperone. The administration of azaperone to horses was confirmed by GC/MS identification of 5'-hydroxyazaperone and 5'-hydroxyazaperol from basic extracts of horse urine treated with beta-glucuronidase/sulfatase. The extracted metabolites were treated with bis(trimethylsilyl)acetamide to produce trimethylsilyl (TMS) ether derivatives, and mass spectra and retention times were compared to those of the synthesized metabolites treated in the same manner.

Summary The pharmacokinetics and metabolism of doxapram in horses administered intravenous (iv) doses of 0.275, 0.55 and 1.1 mg doxapram/kg bodyweight (bwt) were investigated. Plasma doxapram concentrations decreased rapidly after drug administration and the disappearance of doxapram from plasma was best described by a polyexponential equation. Median values of total body clearance were 10.9, 10.6 and 10.9 ml/min/kg bwt for the three doses and were independent of dose. The steady‐state volume of distribution was approximately 1,200 ml/kg bwt and the median biological half‐life ranged from 121 to 178 mins. Plasma protein binding of doxapram ranged from 76.0 to 85.4 per cent. The blood:plasma doxapram concentration ratio was approximately 0.8 and the affinity of the red blood cells for doxapram ranged from 2.0 to 2.8 indicating sequestration of doxapram in erythrocytes. Renal clearance of doxapram was a minor route of elimination. Metabolic clearance of doxapram appeared to be a major route of elimination. Four metabolites of doxapram were isolated from urine and were identified. The metabolites were: a) 1‐ethyl‐4‐[(2‐hydroxyethyl) amino]ethyl‐3,3‐diphenyl‐2‐pyr‐rolidinone, b) a glucuronic acid or sulphuric acid conjugate of 1‐ethyl‐3‐(hydroxyphenyl)‐4‐(2‐morpholinoethyl)‐3‐phenyl‐pyr‐rolidinone, c) 3,3‐diphenyl‐4‐(2‐morpholinoethyl)‐2‐pyr‐rolidinone and d) 1‐(2‐hydroxyethyl)‐3,3‐diphenyl‐4‐(2‐morpholinoethyl)‐2‐pyr‐rolidinone. The rapid disappearance of doxapram from plasma immediately after iv administration was attributed to redistribution of the drug from plasma to other tissues. The short duration of clinical effect from doxapram may be attributed to redistribution of the drug from plasma and other well‐perfused tissues, such as the brain, to less well‐perfused tissues such as the skeletal muscles and adipose tissue. Continuous or repeated administration of doxapram could prolong the duration of clinical effect because re‐distribution is less important as steady‐state conditions are approached.