title: A physiologically based pharmacokinetic model for inhaled carbon tetrachloride.
abstract: D.J. Paustenbach et al. (1986, Fundam. Appl. Toxicol. 6, 484-497) have described the pharmacokinetics of inhaled, radiolabeled carbon tetrachloride (14CCl4) in male Sprague-Dawley rats exposed for 8 or 11.5 hr/day for 1- or 2-week periods. These studies provided time-course information for exhaled 14CCl4, the exhaled 14CO2 metabolite, and 14C radioactivity eliminated in the feces and urine. A physiologically based pharmacokinetic (PB-PK) model which incorporated partition characteristics of CCl4 (blood:air and tissue:blood partition coefficients), anatomical and physiological parameters of the test species (body weight, organ weights, ventilation rates, blood flows, etc.), and biochemical constants (Vmax and Km) for CCl4 metabolism was developed to describe these results. The PB-PK model accurately predicted the behavior of CCl4 and its metabolites, both the exhaled CCl4 and 14CO2 and the elimination of radioactivity in urine and feces. The metabolism of CCl4, determined by gas uptake studies, was adequately described by a single saturable pathway. Metabolites were partitioned in the model to three compartments; the amounts to be excreted in the breath (as 14CO2), urine, and feces. Of total CCl4 metabolism, 6.5, 9.5, and 84.0% were formed via the degradative pathways leading to CO2, urinary, and fecal metabolites, respectively. The simplest kinetic explanation of the metabolite time course is that 4% of the initially metabolized CCl4 is directly converted to CO2 (probably via a chloroform intermediate) and the remainder of metabolized CCl4 binds to biological substrates. These adducts appear to be slowly degraded with an average half-life of 24 hr. The breakdown products subsequently appear in the feces and urine (the rate constant for elimination by these two routes is similar) and a small portion is converted all the way to CO2. The PB-PK model successfully described the elimination by all four routes for all four exposure scenarios using a single set of parameters. Vmax and Km were, respectively, 0.65 mg/kg/hr and 0.25 mg/liter. There was no evidence for loss of Vmax with repeated exposure, as would be expected if there was enzyme destruction at these concentrations of CCl4. The model was scaled-up to predict the expected behavior of parent CCl4 in monkeys and humans and the resulting simulations compared very favorably with data collected by McCollister et al. (1951) and Stewart et al. (1961). On the basis of this model and the published data on the rat at 100 ppm about 60% of the inhaled CCl4 is metabolized and the resulting blood levels are already in excess of saturation for the metabolizing enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000280:Administration, Inhalation; D000818:Animals; D001944:Breath Tests; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002302:Cardiac Output; D005243:Feces / Q000032:analysis; D000882:Haplorhini; D006801:Humans; D008297:Male; D008954:Models, Biological; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
chemical_list: D002251:Carbon Tetrachloride