The two-compartment recirculatory pharmacokinetic model'an introduction to recirculatory pharmacokinetic concepts  Upton R.N.   British Journal of Anaesthesia  Volume 92, Issue 4, Pages 475-484 (April 2004) DOI: 10.1093/bja/aeh089 Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 1 A traditional two-compartment mamillary model. The central compartment (Vc) includes blood (drug concentration Cblood), and transfer of drug to the peripheral compartment is governed by rate constants k12 and k21. R0 and Cl are the drug infusion rate and clearance, respectively. British Journal of Anaesthesia 2004 92, 475-484DOI: (10.1093/bja/aeh089) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 2 (a) A two-compartment recirculatory model. In contrast to Figure 1, the central compartment has been defined as the lungs, with the peripheral compartment as the remainder of the body (less the lungs). This necessitates defining two sites within the blood stream'arterial and mixed venous. The rate constants have been replaced by the apparent distribution volumes of the compartments (VL and VB) and a cardiac output (Q˙CO) term. Clearance has been renamed from Cl to Q˙Cl in keeping with the fact that clearance also has the units of flow of blood. R0 is the drug infusion rate. (b) The non-recirculating version of the model used to calculate the first-pass concentrations. British Journal of Anaesthesia 2004 92, 475-484DOI: (10.1093/bja/aeh089) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 3 An example showing the relationship between first-pass and total drug concentrations for a short infusion (tD=5 min) of a hypothetical high clearance induction agent. The other parameter values were D=100 mg, Q˙CO=5 litre min−1, VL=2.5 litre, VB=15 litre and Q˙Cl=2 litre min−1. If the infusion was continued, the total arterial concentration would continue to increase towards its steady-state value of 10 mg litre−1. British Journal of Anaesthesia 2004 92, 475-484DOI: (10.1093/bja/aeh089) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 4 The effect of cardiac output on the time-course of the first-pass and total concentrations of a drug in arterial and mixed venous blood after i.v. bolus administration of the hypothetical drug. The dose (D) was 100 mg and tD was 30 s. The cardiac output (Q˙CO) was 3, 6, and 9 litre min−1 as indicated. The other parameter values were VL=2.5 litre, VB=15 litre and Q˙Cl=2 litre min−1 and are representative of a high-clearance i.v. induction agent. The steady-state values of the first-pass arterial concentrations, Ca.f(ss), are also stated (equation (5)). The ratio of tD/τ (where τ is the time constant for the lungs) indicates how close the first-pass arterial concentrations at the end of the injection are to their steady-state value. A value of 3 indicates approximately 95% equilibration. British Journal of Anaesthesia 2004 92, 475-484DOI: (10.1093/bja/aeh089) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 5 The effect of the injection time (tD) of a fixed bolus dose (D=100 mg) of the hypothetical drug on the time-course of its first-pass and total concentrations in arterial and mixed venous blood. The injection time was 10, 30, or 120 s as indicated. The other parameter values were Q˙CO=5 litre min−1, VL=2.5 litre, VB=15 litre, and Q˙Cl=2 litre min−1 and are representative of a high-clearance i.v. induction agent. The steady-state values of the first-pass arterial concentrations, Ca.f(ss), are also stated (equation (5)). The ratio of tD/τ indicates how close the first-pass arterial concentrations at the end of the injection are to their steady-state value. A value of 3 indicates approximately 95% equilibration. British Journal of Anaesthesia 2004 92, 475-484DOI: (10.1093/bja/aeh089) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 6 An example showing the relationship between first-pass, recirculated, and total arterial drug concentrations for an infusion (tD=60 min) of the hypothetical drug when cardiac output was variable. In this case, the mean cardiac output was 5 litre min−1, but it oscillated with a period of 4 min and a peak to peak amplitude of 35%. The other parameter values were D=360 mg, VL= 2.5 litre, VB=15 litre, and Q˙Cl=2 litre min−1. Note that the first-pass concentrations were acutely affected by changes in cardiac output, but these concentrations were essentially present only during the intra-infusion period. The recirculated concentrations were less affected by the cardiac output, but persisted into the post-infusion period. The total concentrations (first-pass+recirculated) were therefore variable during the infusion, but less so afterwards. British Journal of Anaesthesia 2004 92, 475-484DOI: (10.1093/bja/aeh089) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 7 The lines of best fit for both a two-compartment recirculatory model, and a two-compartment mamillary model for the same previously published data (symbols) on the thiopental concentrations in arterial blood (mean of five sheep) during and after the infusion of 500 mg over 2 min.20 Both models provided excellent fits of the data (Table 3). British Journal of Anaesthesia 2004 92, 475-484DOI: (10.1093/bja/aeh089) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions