A physiologically based toxicokinetic description of the metabolism of inhaled gases and vapors: Analysis at steady state

Abstract

In studying the kinetics of metabolism of inhaled gases and vapors the rate of metabolism is estimated as a function of inhaled concentration. In the past, pharmacokinetic modeling has been routinely conducted by fitting these data to linearized forms of the Michaelis-Menten (M-M) equation to estimate V max and an apparent inhalation K m . We have determined rate curves for benzene and halothane in rats. These curves were not smooth M-M hyperbolas. They had extended first-order portions, up to greater than 80% V max, and abruptly converted to zero-order dependencies. In addition, achieved steady-state blood:gas concentration ratios have been shown to be variable with respect to inhaled concentration, and maximum rates of metabolism for a wide variety of chemicals were found to cluster toward a common value. These phenomena are difficult to reconcile with the M-M description above. To describe this observed steady-state and kinetic behavior, one must consider enzymatic (biochemical) constants, blood flow to metabolizing organs, and limitations to pulmonary equilibration caused by extensive systemic metabolism. A physiologically based kinetic model for metabolism of inhaled gases and vapors has been developed incorporating these factors and relying on clearance terminology to analyze steady-state behavior. One parameter important in the steady-state formulation is C max-the maximum transhepatic concentration gradient sustainable at a given hepatic blood flow, Q̇ L. C max is equal to V max/Q̇ L. The model shows that M-M hyperbolas are only expected when the affinity of the metabolizing enzyme is low ( K m large) with respect to C max. When affinity is high ( K m small) with respect to C max, abrupt first-order to zero-order transitions are expected. This is the concentration range where organ perfusion, not biochemical constants, is rate limiting. When perfusion is rate-limiting, observed steady-state blood:gas concentration ratios will be lower than predicted by the thermodynamic partition coefficient, and increasing the number of enzymatic centers by induction will not increase the rate of metabolism of inhaled chemical. To properly interpret results of inhalation experimentation one must understand both the role of various physiological factors in controlling the rate of metabolism of inhaled gases and vapors in vivo and the conditions under which perfusion and other physiological factors become rate-limiting.