A Noninvasive In Vivo Method of Assessing the Kinetics of Halothane Metabolism in Humans

Abstract

The authors describe a noninvasive method of estimating the kinetic constants that characterize metabolism of inhaled anesthetics in humans. Ten healthy male volunteers breathed subanesthetic concentrations of halothane and isoflurane in a fixed inspired ratio of 20:1. Isoflurane served as a marker that identified changes in uptake in nonmetabolizing depots. Each study progressed through nine 30-min levels (numbered 0-8). At each level, inspired concentrations of both halothane and isoflurane were doubled, and alveolar concentrations and uptakes were determined. Clearance (uptake/alveolar concentration) of isoflurane remained constant over a range of concentrations of 0.00006 to 0.008%. In contrast, clearance of halothane decreased as the alveolar concentration increased from 0.0007 to 0.13%. On this basis, the authors assumed that the clearance of halothane was a combination of linear clearance to depots and saturable metabolism, the former proportional to the clearance of isoflurane, and the latter attributable to a Michaelis-Menten process. Applying such a model to halothane, they estimated the mean (+/- SE) Vmax (the composite maximum rate of metabolism) to be 0.79 +/- 0.09 ml . min-1 . individual-1, and the Km (the composite concentration at which half-saturation of enzymes occurs) to be 0.029 +/- 0.003%. This model provides a significantly better data fit than that provided by two simpler submodels, one of which assumes that all clearance is linear, and the other of which allows a part of clearance to be saturable but ignores the isoflurane marker data. The value of 0.029% for Km indicates that a wide range of clinical anesthetic concentrations will produce similar rates of metabolism; that metabolism will proceed at near maximum rates during the first several minutes of recovery; and that most metabolism probably occurs after, rather than during, anesthesia.