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

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Abstract
A noninvasive method of estimating the kinetic constants that characterize metabolism of inhaled anesthetics in humans is described. 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 concentrations 0.00006-0.008%. Halothane clearance decreased as the alveolar concentration increased from 0.0007 to 0.13%. Evidently, the clearance of halothane was a combination of linear clearance of 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 showed the mean Vmax (the composite maximum rate of metabolism) to be 0.79 .+-. 0.09 ml/min per individual 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 2 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 1st several minutes of recovery, and most metabolism probably occurs after, rather than during, anesthesia.