Cardiac output influences the pharmacokinetics, including k(e0), for rocuronium in patients. For drugs with a fast onset of effect, a recirculatory model, which includes CO, can give a good description of the relation between concentration and effect, in contrast to a conventional compartmental pharmacokinetic model.

Recirculatory modeling of ICG allows modeling of the first-pass pulmonary kinetics of propofol concurrently. Propofol undergoes extensive uptake and first-pass elimination in the lungs.

Cardiac output markedly influences the pharmacokinetics of alfentanil in pigs. Therefore, accounting for CO enhances the predictive value of pharmacokinetic models of alfentanil.

1 The purpose of the present investigation was to quantify rapid functional adaptation in the concentration-pharmacological eect relationship of alfentanil in rats using quantitative EEG parameters as a pharmacodynamic endpoint. Three groups of 6 ± 7 rats received in a randomized fashion two consecutive infusions of 2.00, 3.14, or 4.24 mg/kg 71 of alfentanil in 20, 40 or 60 min, respectively. The EEG was continuously recorded and frequent arterial blood samples were collected for determination of the alfentanil concentration by gas chromatography. 2 The pharmacokinetics of alfentanil were most adequately described by a bi-exponential function. The values (mean+s.e., n=20) of clearance, volume of distribution at steady-state and terminal half-life were 45+3 ml.min and 23+1 min, respectively, and independent of the administered dose. 3 Increase in power in the 0.5 ± 4.5 Hz (delta) frequency band of the EEG was used as the measure of the pharmacological response. By pharmacokinetic-pharmacodynamic modeling the individual concentration-EEG eect relationships of alfentanil were derived which were successfully quanti®ed by the sigmoidal E max pharmacodynamic model. When the results of the ®rst of the two consecutive infusions were compared, no systematic dierences in the pharmacodynamic parameters were observed for the dierent infusion rates. The averaged values of the pharmacodynamic parameters of alfentanil were (mean+s.e., n=20): E 0 =56+3 mV, E max =93+8 mV, EC 50 =235+27 ng.ml 71 and Hill factor=1.6+0.1, respectively. For the second of the two consecutive infusions a signi®cantly higher value of the EC 50 of 404+56 ng.ml 71 was observed (P50.05), while the values of the other pharmacodynamic parameters were unchanged. Simulations according to a mechanism-based model indicated that the observed change in concentration eect relationship can be explained by a 40% loss of functional m-opioid receptors. 4 The results of the present study show that upon the administration of a single intravenous dose, acute functional adaptation does not interfere with the assessment of the concentration-EEG eect relationship of alfentanil. Upon repeated administration however functional adaptation may be a complicating factor.

When population pharmacokinetic models are used for individualization of dosing schedules, physiologic covariates, e.g., cardiac output, can improve their ability to predict the individual kinetics.