Background: Several recent studies have suggested that the terminal half-lives of many drugs do not predict the rate of washout of drug after the relatively short durations of infusions used in anesthesia. Many anesthetic drugs fit a three-compartment mamillary model, with three volumes of distribution (central [V1] and peripheral [V2 and V3]) and three clearances (elimination or metabolic [Cl1] and distribution [Cl2 and Cl3]). It has been suggested that a large V3:Cl3 ratio contributes to rapid recovery after infusion. We investigated the role of each of these primary pharmacokinetic parameters to determine values of each that would contribute to rapid recovery after various dosing schemes.
Methods: Three sets of computer simulations were performed based on a three-compartment mamillary model for fentanyl, alfentanil, and sufentanil. Set I predicted the change in plasma concentration of each drug after a bolus if each pharmacokinetic parameter were independently increased by 5%. Set II predicted the time for an 80%, 50%, or 20% decrease in plasma concentration after infusions of varying duration (the 80%, 50%, and 20% decrement time, respectively) if each pharmacokinetic parameter were independently increased by 5%. Set III calculated the percent change in each pharmacokinetic parameter alone that would give a 30% shorter decrement time after infusions of varying duration.
Results: Set I demonstrated that after a bolus dose to obtain identical initial plasma concentrations, the drug with a larger V1 had a higher plasma concentration than did the parent drug at all subsequent times. The drug with a larger Cl1 had a lower plasma concentration than did the parent drug at all times. A larger V2, V3, Cl2, or Cl3 led to a lower plasma concentration at times soon after the bolus and subsequently to a higher plasma concentration than did the parent drug. Set II demonstrated that after an infusion, increasing V1 led to a longer decrement time and increasing Cl1 led to a shorter decrement time for infusions of all durations. Increasing V2, V3, Cl2, or Cl3 led to a shorter decrement time when the infusion had been short and when a small decrease in plasma concentration was desired. Increasing each of these four parameters led to a longer decrement time when the infusion had been long and when a larger decrease in plasma concentration was desired. Set III demonstrated that a smaller V1 or a larger Cl1 always led to a shorter decrement time. For infusions of short duration and for a small decrease in plasma concentration, a larger V2, V3, Cl2, or Cl3 led to the desired decrease in decrement time. For infusions of longer duration and for larger decreases in plasma concentration, a smaller V2, V3, Cl2, or Cl3 was able to decrease the decrement time by 30%.
Conclusions: This study proposes qualitative guidelines for pharmacokinetic properties desirable in anesthetic drugs. If a rapid decrease in plasma concentration is desired after an infusion, it is always beneficial to have a small V1 and a large Cl1. For infusions of short duration, after which only a small decrease in plasma concentration is required, it is beneficial to have a larger V2, V3, Cl2, and Cl3. For infusions of longer duration, after which a large decrease in plasma concentration is desired, it is beneficial to have a smaller V2, V3, Cl2, and Cl3. These proposals may be beneficial for planning clinical trials of new drugs.