Fred Boer

First-pass lung uptake and pulmonary clearance of propofol: Assessment with a Recirculatory indocyanine green pharmacokinetic model

BACKGROUND The principal site for elimination of propofol is the liver. The clearance of propofol exceeds hepatic blood flow; therefore, extrahepatic clearance is thought to contribute to its elimination. This study examined the pulmonary kinetics of propofol using part of an indocyanine green (ICG) recirculatory model. METHODS Ten sheep, immobilized in a hammock, received injections of propofol (4 mg/kg) and ICG (25 mg) via two semipermanent catheters in the right internal jugular vein. Arterial blood samples were obtained from the carotid artery. The ICG injection was given for measurement of intravascular recirculatory parameters and determination of differences in propofol and ICG concentration-time profiles. No other medication was given during the experiment, and the sheep were not intubated. The arterial concentration-time curves of ICG were analyzed with a recirculatory model. The pulmonary uptake and elimination of propofol was analyzed with the central part of that model extended with a pulmonary tissue compartment allowing elimination from that compartment. RESULTS During the experiment, cardiac output was 3.90+/-0.72 l/min (mean +/- SD). The blood volume in heart and lungs, measured with ICG, was 0.66+/-0.07 l. A pulmonary tissue compartment of 0.47+/-0.16 l was found for propofol. The pulmonary first-pass elimination of propofol was 1.14+/-0.23 l/min. Thirty percent of the dose was eliminated during the first pass through the lungs. CONCLUSIONS 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.

Recirculatory pharmacokinetics and pharmacodynamics of rocuronium in patients: the influence of cardiac output.

BackgroundRecirculatory models are capable of accurately describing first-pass pharmacokinetics and the influence of cardiac output (CO), which is important for drugs with a fast onset of effect. The influence of CO on pharmacokinetic and pharmacodynamic parameters of rocuronium in patients was evaluated using a recirculatory pharmacokinetic model. MethodsFifteen patients were included to study rocuronium pharmacokinetics and pharmacodynamics. Bolus doses of rocuronium (0.35 mg/kg) and indocyanine green (25 mg) were injected simultaneously via a peripheral intravenous catheter. Blood samples were taken for 240 min from the radial artery. The force of contraction of the adductor pollicis after a train-of-four at 2 Hz every 12 s was measured. Arterial concentration–time curves of rocuronium and indocyanine green were analyzed using a recirculatory model. Pharmacodynamics were described using a sigmoid maximum effect (Emax) model. ResultsThe CO of the patients varied from 2.43 to 5.59 l/min. Total distribution volume of rocuronium was 17.3 ± 4.8 l (mean ± SD). The CO showed a correlation with the fast tissue clearance (ClT_f; r2 = 0.51), with the slow tissue clearance (ClT_s; r2 = 0.31) and with the mean transit times of rocuronium except for the mean transit time of the slow tissue compartment. The blood–effect site equilibration constant (ke0) was strongly correlated with CO (r2 = 0.70). ConclusionsCardiac output influences the pharmacokinetics, including ke0, 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 and compartmental pharmacokinetic modeling of alfentanil in pigs: the influence of cardiac output.

BACKGROUND Cardiac output (CO) is likely to influence the pharmacokinetics of anesthetic drugs and should be accounted for in pharmacokinetic models. The influence of CO on the pharmacokinetic parameters of alfentanil in pigs was evaluated using compartmental and recirculatory models. METHODS Twenty-four premedicated pigs were evaluated during halothane (0.6-2%) anesthesia. They were assigned randomly to one of three groups. One group served as control. In the other groups, the baseline CO was decreased or increased by 40% by pharmacologic intervention (propranolol or dobutamine). Boluses of alfentanil (2 mg) and indocyanine green (25 mg) were injected into the right atrium. Blood samples were taken for 150 min from the right atrium and aortic root. Arterial concentration-time curves of indocyanine green and alfentanil were analyzed using compartmental models (two-stage and mixed-effects approach) and a recirculatory model, which can describe lung uptake and early distribution. RESULTS The CO of individual pigs varied from 1.33 to 6.44 l/min. Three-compartmental modeling showed that CO is a determinant of the central compartment volume (V1, r2 = 0.54), fast peripheral compartment volume (V2, r2 = 0.29), steady state distribution volume (Vss, r2 = 0.29), fast distribution clearance (Cl12, r2 = 0.39), and elimination clearance (Cl10, r2 = 0.51). Recirculatory modeling showed that CO is a determinant of total distribution volume (r2 = 0.48), elimination clearance (r2 = 0.54), and some distribution clearances. The pulmonary distribution volume was independent of CO. CONCLUSIONS Cardiac output markedly influences the pharmacokinetics of alfentanil in pigs. Therefore, accounting for CO enhances the predictive value of pharmacokinetic models of alfentanil.

Modeling population pharmacokinetics of lidocaine: should cardiac output be included as a patient factor?

BackgroundInclusion of cardiac output and other physiologic parameters, in addition to or instead of, demographic variables might improve the population pharmacokinetic modeling of lidocaine. MethodsThirty-one patients were included in a population pharmacokinetic study of lidocaine. After bolus injection of lidocaine (1 mg/kg), 22 or 10 blood samples per patient were taken from a radial artery. During the experiment, cardiac output was measured using a thoracic electrical bioimpedance method. The following four population pharmacokinetic models were constructed and their performances investigated: a model with no covariates, a model with cardiac output as covariate, a model with demographic covariates, and a model with both cardiac output and demographic characteristics as covariates. Model discrimination was performed with the likelihood ratio test. ResultsInclusion of cardiac output resulted in a significant improvement of the pharmacokinetic model, but inclusion of demographic covariates was even better. However, the best model was obtained by inclusion of both demographic covariates and cardiac output in the pharmacokinetic model. ConclusionsWhen 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.

Pulmonary distribution of alfentanil and sufentanil studied with system dynamics analysis

We applied a system dynamics approach to the study of the pulmonary distribution of alfentanil and sufentanil in anesthetized pigs and patients, respectively. This method allows estimation of the mean transit time through the lungs and calculation of the volume of distribution of alfentanil in the lungs. In the first part of the study the pulmonary distribution of alfentanil was studied in six anesthetized pigs during three hemodynamic states (control, partial clamping of the inferior vena cave, and complete clamping of the right pulmonary artery). In the second part of the study the pulmonary distribution of sufentanil was studied in 10 patients, scheduled for elective CABG, during and after a constant rate infusion of 10 min. Pulmonary passage of the opioids was characterized by functions of transit times, derived from the pulmonary arterial and systemic arterial concentration curves. Pulmonary distribution volumes were calculated from the mean transit time and pulmonary blood flow. Pulmonary distribution volume of alfentanil during the control measurement was significantly higher (486±88 ml) than during either partial caval clamping (346±89 ml, p<0.05) or right pulmonary artery clamping (336±56 ml, p<0.05). There was no change in the extravascular volume of distribution of alfentanil with each hemodynamic state. Pulmonary volume of distribution of sufentanil in the patients was 22.6 (10.9) L. Pulmonary distribution of opioids can be studied using system dynamics analysis, both after bolus injection and during and after infusion. This method can be used for periods beyond the initial passage of the drug through the lungs.

Cardiovascular and pulmonary interactions in pharmacokinetics

The fate of drugs in the body is dependent on the physical transport processes in the body. These transport processes are initiated by the flow of blood in the greater and lesser circulation by which the drug is carried to the organs and tissues, where the drug is taken up by active and passive transport mechanisms. The blood flow therefore plays an important role in the initial distribution of drugs and the extend of distribution of the drug within a certain time frame. The influence of the hemodynamic system and the lungs can be modeled, using pharmacokinetic models.