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Vol. 281, Issue 1, 226-232, 1997
Departments of Pharmacology and Clinical Pharmacology, Glaxo Wellcome Inc., Research Triangle Park, North Carolina (J.F.H., M.K.J., K.T.M.), and Department of Anesthesiology, University of Illinois at Chicago, Chicago, Illinois (F.C., W.E.H.)
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Abstract |
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 Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Remifentanil is an esterase-metabolized opioid developed for use in anesthesia. The principal metabolite of remifentanil, GR90291, is considered to be less potent. This study determined the relative potency of GR90291 and alfentanil, compared with remifentanil, in anesthetized dogs. Male dogs received thiamylal sodium, and anesthesia was maintained using isoflurane and N2O in oxygen. Each dog received a 5-min infusion of 0.5 µg/kg/min remifentanil, 500 µg/kg/min GR90291 and 1.6 mg/kg/min alfentanil in random order, separated by 1 week. Serial blood samples were collected during and after the infusion. The electroencephalogram was evaluated using aperiodic analysis. The pharmacokinetics and pharmacodynamics of remifentanil, GR90291 and alfentanil were determined using nonlinear least-squares regression analysis. Remifentanil was rapidly eliminated, with a terminal half-life of 6 min, compared with 19 min for GR90291 and alfentanil. Using the estimated concentration that elicits 50% of the maximum response (EC50) for delta EEG activity and spectral edge95, remifentanil was 4213 to 4637 times more potent than GR90291 and 7.7 to 8.5 times more potent than alfentanil. The blood-brain equilibration half-life was 2.3 to 5.2 min for remifentanil, 0.39 to 0.41 min for GR90291 and 3.1 to 3.7 min for alfentanil.
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Introduction |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Remifentanil hydrochloride is an
esterase-metabolized opioid for use in clinical anesthesia. Previous
studies have shown remifentanil to produce analgesic activity in rats
and humans (Schuster et al., 1991
; Glass et al.,
1993). Chemically, remifentanil contains a methyl ester group that
renders it susceptible to rapid metabolism by blood and tissue
esterases (Feldman et al., 1991). Based on in
vivo and in vitro animal models (rat tail withdrawal or
electrically stimulated guinea pig ileum), the principal metabolite of
remifentanil, GR90291, was previously estimated to be 1/300 to 1/1000th
as potent as remifentanil (James, 1994).
Quantitative analysis of the EEG has been used as a measure of opioid
activity and as a comparative assessment for potency with other opioid
derivatives (Bovill et al., 1983; Scott et al., 1985, 1991; Hoffman et al., 1993). These studies have shown
that opioids produce a characteristic slowing of the EEG. The EEG
waveform can be processed to obtain delta EEG activity and spectral
edge band (Scott et al., 1991; Hoffman et al.,
1993). Delta EEG activity is the EEG energy contained within the
frequency band of 0.5 to 3 Hz, and spectral edge95 is the
frequency below which 95% of the EEG energy is contained.
GR90291 is eliminated primarily by the kidneys. Therefore, after an infusion of remifentanil in patients with compromised renal function, the opioid activity of GR90291 may become clinically relevant. A separate study was conducted to evaluate the effect of severe renal impairment on the pharmacokinetics of remifentanil and GR90291. The purpose of the present study was to use EEG measures of opioid activity to determine the potency of GR90291, relative to remifentanil, in anesthetized dogs. The relative potency information, together with the pharmacokinetics of GR90291 in patients, was important for evaluating the need for remifentanil dose adjustment in patients with renal impairment.
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Materials and Methods |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Study design. This study was approved by the institutional review board for animal research at the University of Illinois at Chicago. Male purpose-bred mongrel dogs (26.0-34.5 kg) were housed under a 12-hr light/dark cycle, with access to food once each day and with water available ad libitum. Dogs received i.v. thiamylal sodium (35 mg/kg), and anesthesia was initiated with 2% isoflurane and 50% nitrous oxide in oxygen after endotracheal intubation. Neuromuscular blockade was achieved using vecuronium (0.01 mg/kg/hr i.v.). A rectal thermistor probe was used to monitor body temperature, which was maintained at 40 ± 1°C. On the first treatment day, chronically indwelling catheters were implanted in the femoral artery and vein. The catheters were guided s.c. to the dog's back and externalized through a small incision. After instrumentation was completed, the end-tidal isoflurane concentration, measured using a Datex anesthetic analyzer (Datex, Helsinki, Finland), was adjusted to 1% (0.7 minimum alveolar concentration) with 50% nitrous oxide in oxygen. Dogs were allowed to stabilize for a minimum of 30 min before infusion of study drugs. Blood gases were measured every 30 min, and end-tidal CO2 was maintained constant (pACO2, 35-40 mm Hg). On the subsequent treatment days, the same anesthetic protocol was followed.
Bipolar needle electrodes were placed bilaterally in the skin for parieto-temporal EEG recording using a Life Scan monitor (Neurometrics, San Diego, CA). This system extracts the wave, frequency and amplitude information from the EEG waveform using aperiodic analysis. A squared function of the electrical amplitude was determined within each of the following frequency bands: 0.5 to 3 Hz (delta waves), 3.1 to 8 Hz (theta waves), 8.1 to 12 Hz (alpha waves) and 12.1 to 30 Hz (beta waves). The fraction of activity of each band in relation to the total electrical activity was determined. Data were averaged over 1-min epochs. Spectral edge95 was calculated as the frequency below which 95% of the EEG power was contained, and delta EEG activity was determined as the total energy contained within the delta frequency band (Scott et al., 1991; Hoffman et al., 1993).
The EEG waveform was allowed to stabilize in each dog before
administration of study drugs. As a result of technical difficulties,
EEG data were not available for all drug treatments in some dogs. Table
1 lists the dogs and drug treatments for which EEG data
were available for pharmacodynamic evaluation.
|
) and alfentanil (Hall et
al., 1994) have been shown to reduce enflurane minimum alveolar
concentration by 50% in dogs. Alfentanil was infused as a comparator
agent for assessing the reliability of the EEG analysis in estimating
the relative potencies of GR90291 and remifentanil. The dose of GR90291 was chosen to be comparable to the dose of remifentanil, based on a
1/1000th relative potency from the previous animal models. Arterial
blood samples (5 ml) were collected before the start of the infusion (0 min) and every 1 min during the infusion (1-5 min). After the
infusion, samples were collected every 1 min for 5 min (6-10 min),
every 2 min for an additional 10 min (11-20 min) and then at 25 min
after infusion (30 min).
Remifentanil blood samples required special sample processing because
of the potential for continued hydrolysis after sample collection.
Blood samples were immediately added to a sample tube containing 50%
citric acid solution for stabilization, mixed and stored frozen
until analysis. Before bioanalysis, samples were mixed with
acetonitrile and centrifuged, and 0.1 M sodium acetate buffer, pH 6, was added to the supernatant. Samples were then loaded onto conditioned
solid-phase extraction columns (Bond Elut Certify; Varian, Harbor City,
CA) and rinsed with acetic acid and 2-propanol. Remifentanil was eluted
with 2% ammonium hydroxide solution in ethyl acetate, evaporated to
dryness and reconstituted in ethyl acetate. Concentrations were
determined using a validated gas chromatography/mass
spectrometry/selected ion-monitoring method (Grosse et al.,
1994). The quantitation limit was 0.1 ng/ml and the interassay
coefficient of variation was <16%. Bioanalysis of GR90291 was not
performed for samples collected after administration of remifentanil.
GR90291 concentrations were determined using high-performance liquid
chromatography (Glaxo Wellcome Inc., data on file). Plasma was loaded
onto a conditioned solid-phase extraction column (C8 Bond
Elut; Varian), rinsed with water and acetonitrile and then eluted with
acetonitrile/phosphate buffer, pH 4.0 (1:4). The high-performance liquid chromatography system consisted of a Supelcosil LC-1 column (Supelco, Inc., Bellefonte, PA), a mobile phase of 15% acetonitrile in
0.05 M phosphate buffer, pH 3, and UV detection at 210 nm. The lower
limit of quantitation was 100 ng/ml, with an interassay coefficient of
variation of <13%.
Alfentanil blood samples were mixed with 0.2 M zinc sulfate and
centrifuged, and 0.1 M sodium acetate buffer, pH 6, was added to the
supernatant. Samples were then loaded onto conditioned solid-phase
extraction columns (Bond Elut Certify; Varian) and rinsed with acetic
acid and methanol. Alfentanil was eluted with 2% ammonium hydroxide
solution in ethyl acetate, evaporated to dryness and reconstituted in
ethyl acetate. Concentrations were determined using a gas
chromatography/mass spectrometry/selected ion monitoring method (Jersey
et al., 1993). The limit of quantitation was 1 ng/ml, and
the interassay coefficient of variation was <10%.
Pharmacokinetics and pharmacodynamics.
The pharmacokinetics
and pharmacodynamics of remifentanil, GR90291 and alfentanil were
determined in each dog using nonlinear, least-squares, regression
analysis (PCNONLIN 4.2; SCI Software, Lexington, KY). A
two-compartment, zero-order, infusion model was used to describe the
concentration-time profiles of each compound. The modeling procedure
was conducted using weighting of 1/Y or 1/Y2 or no weighting, as appropriate, where
Y is the predicted value for concentration or EEG.
Pharmacokinetic and pharmacodynamic model selection was based on
inspection of residual plots, the observed and predicted
concentration-time and effect-time profiles and the Akaike information
criterion (Boxenbaum et al., 1974; Yamaoka et
al., 1978). The central compartment volume of distribution, elimination rate constant (k10) and distribution
rate constants (k12 and
k21) were estimated from the pharmacokinetic
modeling. Clearance, steady-state volume of distribution and terminal
half-life were then obtained using standard techniques (Gibaldi and
Perrier, 1982).
). The equilibration half-life was estimated as
ln(2)/ke0. For interested readers,
excellent reviews of effect-compartment modeling and discussion of
certain assumptions required by the model are provided by Holford and
Sheiner (1981, 1982). The technique of effect compartment modeling has
been previously used to assess the relationship between remifentanil
concentrations and changes in the EEG waveform in healthy volunteers
(Egan et al., 1994a).
The EEG effects of each drug were evaluated using a sigmoid
Emax model (Holford and Sheiner,
1982),
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(1) |
is the sigmoidicity factor and Ce
is the concentration of drug at the effect site. The EEG effect of
GR90291 after the remifentanil infusion was assumed to be negligible, based on previous pharmacokinetic and relative potency estimates (Glaxo
Wellcome Inc., data on file).
Delta EEG activity was modeled as an increase from base line, and
spectral edge95 was modeled as a reduction from base line. The potency ratios and corresponding 90% confidence intervals for
remifentanil/GR90291 and remifentanil/alfentanil were estimated after
logarithmic transformation of the EC50 values (SAS version 6.07; SAS, Cary, NC). All pharmacokinetic and pharmacodynamic parameters were presented as mean and S.D., except half-life, which was
expressed as harmonic mean and jackknife S.D. (Lam et al.,
1985).
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Results |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The concentration-time profiles of remifentanil, GR90291 and
alfentanil (fig. 1) were well described by a
two-compartment pharmacokinetic model. Table 2 shows a
summary of the pharmacokinetic parameters for remifentanil, GR90291 and
alfentanil. The mean clearance of remifentanil was 6 times greater than
that of its metabolite GR90291 and 2 times greater than that of
alfentanil in dogs. The mean central compartment volume of distribution
was similar for remifentanil, GR90291 and alfentanil; however, the mean
steady-state volume of distribution of alfentanil was larger than those
of remifentanil and GR90291. The rapid elimination of remifentanil was
evident from the short terminal half-life (5.59 min), compared with
those of GR90291 (19.2 min) and alfentanil (19.9 min).
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The time course of the changes in EEG effect closely correlated with
the changes in drug concentration. An illustration of the overall blood
concentration-EEG effect time course within individual dogs receiving
remifentanil (fig. 2A), GR90291 (fig. 2B) and alfentanil
(fig. 2C) is shown in figure 2. The profiles show the rapid onset and
termination of effect with increasing drug concentration, particularly
for GR90291. The blood concentration-delta EEG activity profile showed
counterclockwise hysteresis, indicative of a temporal dissociation
between the concentration of drug in the blood and the effect site.
Using the same dogs depicted in figure 2, the relationship between
blood concentration and delta wave activity (hysteresis) for
remifentanil, alfentanil and GR90291 is shown in figure
3 (top). For comparison, the hysteresis profiles were
plotted on a logarithmic scale, with EEG effect expressed as percentage
of maximum effect. The temporal delay between blood concentration and
effect was accommodated using ke0 to
predict effect site concentrations, thereby eliminating the hysteresis (fig. 3, bottom). Although not shown graphically, the hysteresis and
collapsed hysteresis profiles were similar for spectral
edge95.
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The pharmacodynamic parameters for delta EEG activity and spectral
edge95 are listed in table 3. Estimates of
were typically >3, indicative of a steep sigmoidal relationship
between effect site concentrations and EEG effect. The mean
equilibration half-life for GR90291 (0.39-0.41 min) was smaller than
those for remifentanil (2.3-5.2 min) and alfentanil (3.1-3.7 min).
Owing to differences in electrode placement and contact impedance, raw
base-line EEG signal strength varied between dogs and between
treatments within dogs. This is observed in the variability of
Eo and Emax (table 3).
Accordingly, for graphical presentation of the three study treatments,
the data were presented as a percentage of the maximum EEG effect.
Figure 4 shows the effect site concentration
vs. delta wave activity, and associated mean
EC50 and S.D., for remifentanil, GR90291 and alfentanil.
Within each treatment group, the profiles show good consistency in
response to the EEG effects of these opioid derivatives.
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Using delta EEG activity, the EC50 values for remifentanil, GR90291 and alfentanil in the presence of 50% N2O and 1% isoflurane anesthesia were 0.97, 4515 and 7.70 ng/ml, respectively. Using spectral edge95, the EC50 values for remifentanil, GR90291 and alfentanil in the presence of 50% N2O and 1% isoflurane anesthesia were 0.64, 2930 and 5.00 ng/ml, respectively. The relative potencies, with corresponding 90% confidence intervals, of GR90291 and alfentanil, compared with remifentanil, are presented in table 4. For descriptive purposes, the potencies of GR90291 and alfentanil are presented relative to a remifentanil potency of unity. Compared with remifentanil, its principle metabolite GR90291 was approximately 1/4600th as potent and alfentanil was approximately 1/8th as potent.
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Discussion |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Opioid derivatives produce a characteristic slowing of the EEG waveform, i.e., formation of delta waves. These EEG changes were used in this study to determine the in vivo relative potency of the principle metabolite of remifentanil, GR90291. Alfentanil was used as a comparator for assessing the reliability of the EEG analysis in estimating the relative potencies of GR90291 and remifentanil. The concentrations of each compound were modeled to characterize the concentration-time profile during the EEG measurement time period. This allowed predicted concentrations to be used in the comparative assessment of the pharmacodynamics of remifentanil, GR90291 and alfentanil.
The pharmacokinetics of remifentanil, GR90291 and alfentanil were well
described using a two-compartment i.v. infusion model. Remifentanil was
rapidly eliminated, with a terminal half-life of 5.59 min, which is
consistent with previous studies in dogs (T1/2, 4-8 min)
(Feldman et al., 1991). GR90291 and alfentanil were
eliminated 3.5 times more slowly, with half-life values of 19 to 20 min. These results are consistent with previous studies in human
volunteers, where the half-life of remifentanil was shown to be about 5 to 8 times more rapid than that of GR90291 and 4 times more rapid than
that of alfentanil (Westmoreland et al., 1993; Egan et
al., 1994b).
Based on in vivo and in vitro animal models,
GR90291 was previously estimated to have 1/300th to 1/1000th the
activity of remifentanil (James, 1994). For this reason, GR90291 was
infused in the dogs at 1000 times the infusion dose of remifentanil, to determine an in vivo potency ratio. Alfentanil was
previously shown to be approximately 20 to 30 times less potent than
remifentanil using analgesic and respiratory effects (Glass et
al., 1993) and 17 times less potent using EEG spectral
edge95 (Egan et al., 1994a), comparing
equipotent concentrations of the drugs in the blood. Because of the
differences in pharmacokinetics of remifentanil, GR90291 and
alfentanil, the evaluation of relative potency was based on
EC50 rather than dose.
As previously noted (Bovill et al., 1983; Scott et
al., 1985, 1991), the EEG proved to be a sensitive and reliable
measure of opioid activity. The characteristic slowing of the EEG
waveform was evident during the infusion of each study drug. Profiles
of the blood concentration vs. EEG activity revealed
hysteresis, indicative of the equilibration delay between the
concentration of drug in the blood and the concentration of drug at the
effect site. Using the methodology developed by Hull et al.
(1978) and Sheiner et al. (1979), a
pharmacokinetic/pharmacodynamic model was used to describe the
relationship between the drug concentration and EEG effects.
The concentration-effect profiles for each drug were adequately described using a sigmoidal Emax pharmacodynamic model, which allowed estimation of the effect site concentration necessary to achieve 50% of the maximum response (EC50). The EC50 values were then used for evaluating the relative potencies of GR90291 and alfentanil, compared with remifentanil.
Visual inspection of the hysteresis and collapsed hysteresis plots
showed good distribution of observed EEG data about the fitted line. In
some instances, the predicted profiles appeared to over- or
underestimate base-line EEG and data collected shortly after initiation
of the infusion. This can be explained by inspection of the EEG time
course profiles (fig. 2). Note that the base line is estimated not only
from EEG data collected before and shortly after initiation of the
infusion but also from a preponderance of EEG data collected after the
infusion, when the response measure had returned to base line. The
value of (sigmoidicity > 3) indicated a steep relationship
between drug concentration and effect. This is also evident from the
collapsed hysteresis profiles (fig. 3, bottom).
As indicated by the estimates for
ke0, the blood-brain equilibration
half-life of GR90291 (0.39-0.41 min) with the hypothetical effect site
was almost 10 times faster than those of remifentanil (2.3-5.2 min)
and alfentanil (3.1-3.7 min). In pharmacokinetics, a rate constant
(k) is a function of clearance (CL) (milliliters per minute) and volume (V) (milliliters). For a given drug,
and assuming constant clearance, the time required to achieve steady state (equilibrium) would be greater as volume increases
(k = CL/V). That is, the drug
would equilibrate faster with a small volume, as opposed to a large
volume. An analogous argument can be constructed using techniques
established for physiological modeling (Bernareggi and Rowland, 1991).
A rate constant (k) can be described in terms of flow
(Q) (milliliters per minute), volume (V)
(milliliters) and the partition coefficient of the drug
(Kp),
|
(2) |
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(3) |
).
Within each dog, the EC50 values for remifentanil, GR90291 and alfentanil using delta EEG activity were typically higher than those estimated using spectral edge95, emphasizing the need to compare "like with like" pharmacodynamic response measures. The EC50 obtained from delta EEG activity was about 1.5 times higher than that estimated using spectral edge95. Using the EC50 values for remifentanil and GR90291, potencies of 1:4637 for delta EEG activity and 1:4213 for spectral edge95 were obtained. Similarly, remifentanil to alfentanil potencies of 1:8.5 and 1:7.7 were obtained for delta EEG activity and spectral edge95, respectively. These potency ratios indicate that the principle remifentanil metabolite, GR90291, possesses about 1/4600th the potency of remifentanil and that alfentanil is approximately 1/8th as potent as remifentanil.
Accurate knowledge of the relative potency of GR90291 was important to assess the significance of its accumulation in humans. Because the primary route of elimination of GR90291 is by the kidneys and because GR90291 shows a potency that is 4600 times less than that of remifentanil, the opioid effects of GR90291 may assume importance only during prolonged, high-dose infusions of remifentanil in anephric patients.
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Footnotes |
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Accepted for publication December 16, 1996.
Received for publication May 14, 1996.
1 This research was conducted at the Department of Anesthesiology, University of Illinois at Chicago (Chicago, IL). This work was supported by Glaxo Wellcome Inc.
Send reprint requests to: J. Frank Hoke, Ph.D., Glaxo Wellcome Development Ltd., 891-995 Greenford Road, Greenford, Middlesex, UB6 0HE, United Kingdom.
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Abbreviations |
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EEG, electroencephalogram; ke0, blood-brain equilibration rate constant.
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References |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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, drug concentrations; 
, delta activity.
