Determination of the kinetic constants for metabolism of inhaled toxicants in vivo using gas uptake measurements

Abstract

Listen

Translate article

Abstract During exposure to inhaled toxicants of low water solubility, blood:gas equilibrium is rapidly attained. Metabolism, tissue loading in poorly perfused organs, and excretion continually reduce in vivo levels, causing further uptake of toxicant. Kinetic parameters for metabolism and tissue loading into poorly perfused tissues can be determined by suitable kinetic analysis of the concentration dependence of the rates of toxicant uptake from recirculated atmospheres. We have investigated the rates of toxicant uptake in rats for (1) Freon 113, (2) Freon 114, (3) difluoroethylene, (4) vinyl methyl ether, (5) 1,1-dichloroethylene, (6) vinyl bromide, (7) ethylene, (8) benzene, (9) bromochloromethane, (10) trichloroethylene, (11) trans -1,2-dichloroethylene, (12) methyl chloride, (13) halothane, (14) methyl bromide, and (15) vinylidene bromide. With (1–3), which have very low water solubility, rates of uptake could not be accurately measured using our chamber design. Rate curves for (4–7) showed a saturable dependence on toxicant concentration. With (8–13) the rate curves had a mixed-form, possessing both a saturable and a first-order component. Rates of uptake with (14 and 15) were rapid and rate curves were first-order. Saturable dependencies appeared to be associated with enzymatic metabolism. Data were transformed by modified Eadie-Hofstee plots to calculate the inhalational K m , the ambient concentration at which uptake proceeded at half the maximum rate, and the inhalational V max , the maximum rate of uptake (i.e., maximum rate of metabolism). First-order uptake appeared either to be tissue loading (10–13) or rapid, nonenzymatic metabolism (14 and 15). A four-compartment, steady-state, pharmacokinetic model was developed to describe gas uptake data in general. Physiological control of the rate of metabolism of inhaled toxicants in vivo was complex. For many of these metabolized toxicants respiration and hepatic perfusion appeared to be rate limiting at low toxicant concentrations, while the capacity of the liver to conduct metabolism was rate limiting at high concentration.