Linearity of pharmacokinetics and model estimation of sufentanil.

BACKGROUND: The pharmacokinetic profiles of sufentanil available in the literature are conflicting because of methodologic differences. Length of sampling and assay sensitivity are key factors involved in accurately estimating the volumes of distribution, clearances, and elimination phase. The unit disposition function of increasing doses of sufentanil were investigated and the influence of dose administered on the linearity of pharmacokinetics was assessed.
METHODS: The pharmacokinetics of sufentanil were investigated in 23 patients, aged 14-68 yr, scheduled for surgery with postoperative ventilation. After induction of anesthesia, sufentanil was administered as a short infusion (10-20 min) in doses ranging from 250 micrograms to 1,500 micrograms. Frequent arterial blood samples were gathered during and at the end of infusion, then at specific intervals up to 48 h after infusion. Plasma concentrations of sufentanil were measured by radioimmunoassay (limit of sensitivity 0.02 ng.ml-1). The data were analyzed with the standard two-stage, naive pooled-data and the mixed effect pharmacokinetic approaches.
RESULTS: The pharmacokinetics of sufentanil were adequately described by a linear three-compartmental mamillary model with the following parameters, expressed as log mean values with 95% confidence intervals: the central volume of distribution = 14.3 l (13.1-15.41), the rapidly equilibrating volume = 63.1 l (61.9-64.3 l), the slowly equilibrating volume = 261.6 l (260.2-262.9 l), the steady-state distribution volume = 339 l (335-343 l), metabolic clearance = 0.92 l.min-1 (0.84-1.05 l.min-1), rapid distribution clearance = 1.55 l.min-1 (1.34-2.14 l.min-1), slow distribution clearance = 0.33 l.min-1 (0.27-0.49 l.min-1), and elimination half-life = 769 min (690-1011 min). No relation to age, weight, or lean body mass was found for any of the parameters.
CONCLUSIONS: Sufentanil pharmacokinetics were linear within the dose range studied. Drug detection up to 24 h after dosing was necessary to define the terminal elimination phase. The metabolic clearance approached liver blood flow and a large volume of distribution was identified, consistent with the long terminal elimination half-life. Simulations predicted that plasma sufentanil steady-state concentrations would rapidly decline after termination of an infusion despite the long half-lives.