What We Already Know about This Topic:

Recirculatory pharmacokinetic models describe intravascular mixing by incorporating cardiac output and its distribution to characterize the oscillations of arterial and venous drug concentrations in the minutes after rapid IV drug administration
Arterial drug concentrations during a drug infusion are higher than venous concentrations but are lower than postinfusion venous concentrations

What This Article Tells Us That Is New:

A ketamine dataset with simultaneously collected arterial and venous blood samples was used to develop an intravascular mixing model that reconciled the divergent arterial and venous concentration versus time relationships during and after drug infusion
Higher arterial concentrations during drug infusion result from the contribution of both partially mixed drug from the upstream infusion and mixed recirculating drug
The partially mixed concentration is proportional to the ratio of the drug infusion rate and cardiac output
Higher postinfusion venous concentrations are due to contributions of drug eluting from tissue

Background: The pharmacokinetics of infused drugs have been modeled without regard for recirculatory or mixing kinetics. We used a unique ketamine dataset with simultaneous arterial and venous blood sampling, during and after separate S(+) and R(–) ketamine infusions, to develop a simplified recirculatory model of arterial and venous plasma drug concentrations.

Methods: S(+) or R(–) ketamine was infused over 30 min on two occasions to 10 healthy male volunteers. Frequent, simultaneous arterial and forearm venous blood samples were obtained for up to 11 h. A multicompartmental pharmacokinetic model with front-end arterial mixing and venous blood components was developed using nonlinear mixed effects analyses.

Results: A three-compartment base pharmacokinetic model with additional arterial mixing and arm venous compartments and with shared S(+)/R(–) distribution kinetics proved superior to standard compartmental modeling approaches. Total pharmacokinetic flow was estimated to be 7.59 ± 0.36 l/min (mean ± standard error of the estimate), and S(+) and R(–) elimination clearances were 1.23 ± 0.04 and 1.06 ± 0.03 l/min, respectively. The arm-tissue link rate constant was 0.18 ± 0.01 min^–1, and the fraction of arm blood flow estimated to exchange with arm tissue was 0.04 ± 0.01.

Conclusions: Arterial drug concentrations measured during drug infusion have two kinetically distinct components: partially or lung-mixed drug and fully mixed-recirculated drug. Front-end kinetics suggest the partially mixed concentration is proportional to the ratio of infusion rate and total pharmacokinetic flow. This simplified modeling approach could lead to more generalizable models for target-controlled infusions and improved methods for analyzing pharmacokinetic-pharmacodynamic data.

Ketamine is a chiral N-methyl-d-aspartate receptor antagonist that is available in pharmaceutical products as either the racemic mixture or as the pure S(+) enantiomer. For more than 50 yr, ketamine has been used as an anesthetic agent (alone or in combination with other agents), but in recent years there has been increasing interest in its use at much lower doses as an adjunct in the treatment of perioperative pain, chronic pain, and treatment-resistant depression.

The pharmacokinetics of ketamine have been the subject of many investigations that have focused on clinically important aspects of pharmacokinetics, such as the differential pharmacokinetics of the R(–) and S(+) enantiomers, pharmacokinetics during target-controlled infusion, comparing the pharmacokinetics of oral versus IV administration, and studying its pharmacokinetic-pharmacodynamic relationships for analgesic, psychotropic, and cardiorespiratory effects, such as increasing cardiac output.

Front-end kinetics are pharmacokinetic models that describe intravascular mixing by incorporating cardiac output and its distribution to characterize the oscillations of arterial and venous drug concentrations in the moments after administration as a rapid IV bolus or as a single-breath thermally generated aerosol. Pharmacokinetic models that are able to describe front-end kinetics are multicompartmental models that yield values for intercompartmental clearances and peripheral distribution volumes that are comparable to those of standard multicompartmental models. However, in these models the traditional single, fully mixed central compartment is a hybrid of the IV administration site, heart, pulmonary blood vessels and tissue, arterial sampling site, nondistributive blood flow, and a central venous sampling site. For ketamine, such a model was used to demonstrate that the R(–) and S(+) enantiomers did not differ in their respective pulmonary uptake or peripheral tissue distribution, although their elimination clearances were different.

Front-end kinetics have mostly been applied to pharmacokinetic studies with rapid drug administration followed by very frequently obtained arterial blood samples. Upton described a simplified two-compartment construct, corresponding to lung and body compartments and arterial and mixed venous drug concentrations, respectively. These concepts could be used when the drug has been administered by infusion and blood samples have been obtained relatively infrequently both during and after the infusion.

In a previous study, arterial and venous blood samples were collected simultaneously during and after a 30-min ketamine infusion, once when R(–) ketamine was administered and once when S(+) ketamine was administered. It was our premise that a front-end kinetic intravascular mixing model would reconcile the divergent arterial and venous ketamine concentration versus time curves and that the distribution kinetics of R(–) and S(+) ketamine are not different. Specifically, we postulated the higher arterial ketamine concentrations during infusion result from the contribution of both unmixed drug from the “upstream” infusion and fully mixed recirculating drug described by front-end pharmacokinetic models and that the systematically slightly higher postinfusion venous ketamine concentrations can be modeled with a contribution of higher drug concentrations eluting from arm tissue. Thus, the purpose of the current study was to build a pharmacokinetic model that incorporated arterial and venous S(+) and R(–) ketamine concentration data.

Ketamine venous versus arterial concentration

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