Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs

Abstract

Elimination half-life is the pharmacokinetic parameter used most commonly to describe duration of pharmacologic action, including that expected of intravenous anesthetic drugs administered by continuous infusion. Little consideration has been given, however, to the relevance of elimination half-life in describing plasma (central compartment) drug concentrations in the context of relevant infusion durations. Therefore, simulations were performed with multicompartment pharmacokinetic models for six intravenous anesthetic drugs. These models had elimination half-lives ranging from 111 to 577 min. The input in each simulation was an infusion regimen designed to maintain a constant plasma drug concentration for durations ranging from 1 min to 8 h and until steady state. The time required for the plasma drug concentration to decline by 50% after terminating each infusion in each of the models was determined and was designated the "context-sensitive half-time," where "context" refers to infusion duration. The context-sensitive half-times were markedly different from their respective elimination half-lives and ranged from 1 to 306 min. The half-times were explained by posing each pharmacokinetic model in the form of a hydraulic model. These simulations demonstrate that elimination half-life is of no value in characterizing disposition of intravenous anesthetic drugs during dosing periods relevant to anesthesia. We propose that context-sensitive half-times are a useful descriptor of postinfusion central compartment kinetics.