Pharmacokinetics and pharmacodynamics of remifentanil in persons with renal failure compared with healthy volunteers.
BACKGROUND
Remifentanil is an opioid analgesic for use in anesthesia. An ester linkage renders it susceptible to rapid metabolism by blood and tissue esterases. Thus it was hypothesized that remifentanil elimination would be independent of renal function. Because its principal metabolite (GR90291) is eliminated renally, it would depend on renal function. This study was designed to evaluate the pharmacokinetics and pharmacodynamics of remifentanil and its metabolite in persons with and without renal failure.


METHODS
Two groups of volunteers received two-stage infusions of remifentanil: low dose with 0.0125 microg x kg(-1) x min(-1) for 1 h followed by 0.025 microg x kg(-1) x min(-1) for 3 h; and high dose with 0.025 microg x kg(-1) x min(-1) for 1 h followed by 0.05 microg x kg(-1) x min(-1) for 3 h. Blood samples were collected for analysis of remifentanil and GR90291 concentrations. The pharmacokinetics of remifentanil were fit using a one-compartment pharmacokinetic model. Remifentanil's effect was determined intermittently using minute ventilation during a hypercapnic (7.5% CO2) challenge.


RESULTS
Fifteen patients with renal failure and eight control participants were enrolled. The clearance and volume of distribution of remifentanil were not different between those with renal failure and the controls. Patients with renal failure showed a marked reduction in the elimination of GR90291; the half-life of the metabolite increased from 1.5 h in the controls to more than 26 h in patients with renal failure. The steady-state concentration of GR90291 is likely to be more than 25 times higher in persons with renal failure. There were no obvious differences in opioid effects on minute ventilation in the controls and in patients with renal failure.


CONCLUSIONS
The pharmacokinetics and pharmacodynamics of remifentanil were not altered in patients with renal disease, but the elimination of its principal metabolite, GR90291, was markedly reduced. Based on simulations, the concentration of GR90291 at the end of a 12-h remifentanil infusion of 2 microg x kg(-1) x min(-1) is not likely to produce significant opioid effects.
Hoke
J F
JF
Glaxo Wellcome, Research Triangle Park, North Carolina, USA.
Shlugman
D
D
Dershwitz
M
M
Michałowski
P
P
Malthouse-Dufore
S
S
Connors
P M
PM
Martel
D
D
Rosow
C E
CE
Muir
K T
KT
Rubin
N
N
Glass
P S
PS
D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D010880:Piperidines / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077208:Remifentanil; D006435:Renal Dialysis; D051437:Renal Insufficiency / Q000378:metabolism*
D000701:Analgesics, Opioid; D010880:Piperidines; C084032:GI 90291; D000077208:Remifentanil