Recirculatory pharmacokinetics. Which physiological covariates affect the pharmacokinetics of intravenous agents?

Thomas K. Henthorn

University of Colorado Health Sciences Center, Denver, CO USA

One of the goals of clinical pharmacology is to understand interindividual differences in response to drugs. Accordingly, great efforts have been made to perform relevant pharmacokineitic-pharmacodynamic (pk-pd) studies of intravenously administered anesthetic drugs. The pattern since the advent of assays capable of measuring plasma drug concentrations, has been to bring state-of-the-art kinetic techniques into the anesthetic arena, only to find them lacking relevance to clinical anesthesia events. This has led investigators to work out new kinetic tools and concepts that have more relevance. There are many examples of this phenomenon. Anesthesiologists invented context-sensitive half time because the concept of half life was irrelevant. They have developed computer controlled infusions to more quickly achieve stable effect-site concentrations. Pk-pd studies published in the anesthesia literature are almost always based on arterial instead of venous blood samples used elsewhere. Anesthesiologists have championed sophisticated analyses of drug interactions that examine synergism as well as optimum drug combinations based on pk considerations.

In this tradition, anesthesia investigators have identified limitations in the study of interindividual variability following IV bolus drug administration. Since most all pk models assume instantaneous mixing in all compartments, it is common to delay arterial blood sampling some 1-3 minutes after IV bolus dosing so that samples obtained before completion of intravascular mixing are avoided and conventional mathematical models can be used which describe a monotonic decline.¹ The problem with this paradigm is that for many IV hypnotics, opioids, and the newer muscle relaxants most, if not all, of the maximum effect is observed before the first plasma sample is obtained. To understand variability during onset of effect, a relevant description of the drug concentration history during the first two minutes following drug administration is essential. The solution to describing the kinetics of intravascular mixing, was the development of the recirculatory model.

The recirculatory pharmacokinetic model is really a hybrid, having structural and functional elements of both physiologic and pharmacokinetic models.² Functionally, a recirculatory model is a pk model as it is strictly a model of the drug concentration vs time curve, not a model of the system per se. This makes the peripheral compartments of a recirculatory model identical to those of traditional pk models. Yet it has some functional aspects of a physiologic model in that cardiac output is estimated by, and retained in, the model. This physiologic aspect is most apparent when viewed structurally as a series of tissue compartments arranged in parallel. However, the recirculatory model bears an equal resemblance to a traditional 3-compartment model if one views the central circuit and the very rapidly equilibrating peripheral circuits (conceptually, pk shunts) as the “inner workings” of V₁. Viewing V₁, not as compartment, but as complex machinery for mixing, that includes first pass pulmonary uptake and some recirulation of drug, is a healthy concept.

What goes on inside V₁ after a bolus injection has been termed the “front-end kinetics.” ³ These events are significant because they include first-pass pulmonary uptake, determine the timing and magnitude of the initial arterial blood drug concentrations seen by the effector sites, and, more importantly, determine the AUC up to, and including, the time to peak effect (approximately 2 minutes). The latter is an important parameter because it best correlates with the size of the peak pharmacologic effect. The single most important physiologic covariate affecting AUC_0-2 is the cardiac output in a direct inverse relationship. ⁴ This makes intuitive sense as cardiac output is estimated from the first-pass AUC, so a continuing flow effect on AUC is not unexpected. An additional factor is the degree to which the pk shunt flow is preserved in many low cardiac output states. Studies utilizing physiologic models in settings in which cardiac output is reduced have tended to arbitrarily reduce blood flow to the various tissues in the model on a uniform basis, proportional to the change in cardiac output.⁵ Instead, we have shown that the changes in flow to various peripheral compartments are not proportional to changes in cardiac output whether these changes are a result of volatile anesthetics⁶ or changes in blood volume ⁷.

Of course, a pk model, no matter how sophisticated, is not of much use by itself. The ultimate plan has always been to perform pk-pd studies in which an accurate description of the front-end kinetics are available in the model. This has finally been accomplished by Fred Boer’s group in Lieden. They were able to show in a human study which combined the recirculatory pks with the pds of rocuronium that k_e0 was related to cardiac output with an r² of 0.70.⁸ These investigators also found the pk-pd analysis to be more robust and predictive when concentrations from the mixing phase where included in the modeling as opposed to when a two compartment pk model was used and early samples were excluded. Most importantly, k_e0 was correlated with age only when recirculatory kinetics where considered. This is exciting news as meaningful pk-pd bases of interindividual differences in drug effect have been difficult to come by. Perhaps many of the answers to clinical pharmacologic questions surrounding IV adminintration lie in the front-end.

1. Fisher DM: (Almost) everything you learned about pharmacokinetics was (somewhat) wrong! Anesth Analg 1996; 83: 901-3

2. Wada, D. R. and Ward, D. S. The hybrid model: a new pharmacokinetic model for computer-controlled infusion pumps. IEEE Transactions on Biomedical Engineering 41(2), 134-42. 94.

3. Krejcie TC, Avram MJ: What determines anesthetic induction dose? It's the front-end kinetics, doctor! Anesth Analg 1999; 89: 541-4

4. Kuipers JA, Boer F, Olofsen E, Olieman W, Vletter AA, Burm AG, Bovill JG: Recirculatory and compartmental pharmacokinetic modeling of alfentanil in pigs: the influence of cardiac output. Anesthesiology 1999; 90: 1146-57

5. Wada DR, Bjorkman S, Ebling WF, Harashima H, Harapat SR, Stanski DR: Computer simulation of the effects of alterations in blood flows and body composition on thiopental pharmacokinetics in humans. Anesthesiology 1997; 87: 884-99

6. Avram MJ, Krejcie TC, Niemann CU, Enders-Klein C, Shanks CA, Henthorn TK: Isoflurane alters the recirculatory pharmacokinetics of physiologic markers. Anesthesiology 2000; 92: 1757-68

7. Krejcie TC, Henthorn TK, Gentry WB, Niemann CU, Enders-Klein C, Shanks CA, Avram MJ: Modifications of blood volume alter the disposition of markers of blood volume, extracellular fluid, and total body water. J Pharmacol Exp Ther 1999; 291: 1308-16

8. Kuipers JA, Boer F, Olofsen E, Bovill JG, Burm AG: Recirculatory Pharmacokinetics and Pharmacodynamics of Rocuronium in Patients: The Influence of Cardiac Output. Anesthesiology 2001; 94: 47-55