Pharmacokinetics of inhaled carbon disulphide in rats in relation to its inhibitory effect on the side-chain oxidation of hexobarbital.

Abstract

In acute inhalational exposure even low doses of carbon disulphide (CS2) inhibit the oxidative drug metabolism: This inhibition, studied by the example from the side-chain oxidation of hexobarbital, increases steadily in adult female rats during exposure to 100 ppm over 8 hrs, as shown by the prolonged hypnotic-narcotic effect; it is completely reversible within 24 hrs so that repeated identical doses of CS2 do not give rise to a cumulative effect. The cause of this phenomenon is an inhibition of the microsomal oxydative enzyme system in the liver, as could be demonstrated in purified enzyme preparations from liver homogenates of rats exposed to 50 ppm CS2 over 2–8 hrs. This inhibitory effect is intimately linked with the presence of CS2 in the organism, as seen from its pharmacokinetic behaviour. In the course of an 8-hr inhalation (400 ppm CS2) the rate of saturation in the blood and liver is most rapid during the first few hours. After the termination of the exposure CS2 is distributed in the blood and liver at a ratio of 3:2. Approximately one third of the CS2 that has passed into the liver is found in the isolated microsomas where it is detectable for several hours. Elimination of the inhaled CS2 from the blood and liver occurs at a halflife of 35 min and 65 min, respectively. The preferred route of elimination is by exhalation, approximately 10% of the14CS2 activity being recovered within 4 hrs following subcutaneous injection of14CS2. Significant oxidation of CS2 to urinary sulphate has not been found to occur after inhalation. Since the inhibition of the microsomal mixed-function oxygenases due to inhaled CS2 occurs primarily during its retention in the organism, it is concluded that initially CS2 itself acts as the inhibitor, but it appears probable that CS2 metabolites (for example, thiurams) are also implicated.