Do distribution volumes and clearances relate to tissue volumes and blood flows? A computer simulation

Kinetics of inhaled agents are often described by physiological models. However, many pharmacokinetic concepts, such as context-sensitive half-times, have been developed for drugs described by classical compartmental models. We derived classical compartmental models that describe the course of the alveolar concentrations (FA) generated by the physiological uptake and distribution models used by the Gas Man program, and describe how distribution volumes and clearances relate to tissue volumes and blood flows. Gas Man was used to generate FA vs. time curves during the wash-in and wash-out period of 115 min each with a high fresh gas flow (8 L x min(-1)), a constant alveolar minute ventilation (4 L x min(-1)), and a constant inspired concentration (FI) of halothane (0.75%), isoflurane (1.15%), sevoflurane (2%), or desflurane (6%). With each of these FI, simulations were ran for a 70 kg patient with 5 different cardiac outputs (CO) (2, 3, 5, 8 and 10 L x min(-1)) and for 5 patients with different weights (40, 55, 70, 85, and 100 kg) but the same CO (5 L x min(-1)). Two and three compartmental models were fitted to FA of the individual 9 runs using NONMEM. After testing for parsimony, goodness of fit was evaluated using median prediction error (MDPE) and median absolute prediction error (MDAPE). The model was tested prospectively for a virtual 62 kg patient with a cardiac output of 4.5 L x min(-1) for three different durations (wash-in and wash-out period of 10, 60, and 180 min each) with an FI of 1.5% halothane, 1.5% isoflurane, sevoflurane 4%, or desflurane 12%. A three-compartment model fitted the data best (MDPE = 0% and MDAPE < or = 0.074%) and performed equally well when tested prospectively (MDPE < or = 0.51% and MDAPE < or = 1.51%). The relationship between CO and body weight and the distribution volumes and clearances is complex. The kinetics of anesthetic gases can be adequately described e by a mammilary compartmental model. Therefore, concepts that are traditionally thought of as being applicable to the kinetics of intravenous agents can be equally well applied to anesthetic gases. Distribution volumes and clearances cannot be equated to tissue volumes and blood flows respectively.