Inhalation pharmacokinetics: evaluating systemic extraction, total in vivo metabolism, and the time course of enzyme induction for inhaled styrene in rats based on arterial blood:inhaled air concentration ratios.

A method is described for evaluating systemic extraction of soluble vapors during inhalation exposures. The physiological basis of the method is the inability to achieve complete equilibrium of vapor between arterial blood and inhaled air whenever there is substantial extraction of the soluble vapor during a single pass through the systemic circulation. The technique was applied to estimate styrene extraction ratios at the end of 6-hr exposures in male rats exposed to various concentrations of inhaled styrene. From extraction ratios and several physiological constants, metabolic constants were evaluated for styrene metabolism in vivo. In naive rats, the maximum velocity of metabolism was 10.0 mg/kg/hr, and Km was of the order of 0.2 mg/liter. Pretreatment with pyrazole (320 mg/kg, 1/2 hr before exposure) essentially abolished in vivo styrene metabolism, while pretreatment with phenobarbital (80 mg/kg/day for the 4 days before styrene exposure) increased Vmax about sixfold. Prior exposure to styrene (1000 ppm for 6 hr/day on each of 4 days before experimentation) increased Vmax by a factor of 2. Significant induction of styrene metabolism in vivo was observed in 24-hr continuous exposure to 400, 600, or 1200 ppm. A curve fitting routine was employed with a physiological model of styrene inhalation kinetics to estimate the dynamics of the induction process in the 24-hr exposures. At 400 ppm, induction began after a lag of 15.5 hr, had a half-life of 3.5 hr, and reached 2.7 times the Vmax in naive rats. At 600 ppm, it began after 10.6 hr, proceeded with a half-life of 2.2 hr, and increased Vmax by 3.4 times. At 1200 ppm, induction began earlier, 4.6 hr, and reached a greater value, 4.4 times Vmax, but had a half-life similar to that at 600 ppm. No induction occurred in 48-hr exposure to 200 ppm. Induction complicates kinetic modeling of continuous inhalation with soluble, well-metabolized vapors because it is time and concentration dependent. These methods should prove useful for studying the in vivo metabolism of other soluble, well-metabolized vapors and for examining the time course of induction of the metabolizing enzymes for these chemicals.