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Vol. 293, Issue 2, 646-653, May 2000
)-O-Desmethyltramadol, in Rats1
Department of Pharmacology, School of Medicine, University of Basque Country, Leioa, Bizkaia (M.V., M.J.G., J.M.P, R.C.); and Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, Pamplona (I.F.T.), Spain
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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The pharmacokinetics and pharmacodynamics of the two main metabolites
of tramadol, (+)-O-desmethyltramadol and
(
)-O-desmethyltramadol, were studied in rats.
Pharmacodynamic endpoints evaluated were respiratory depression,
measured as the change in arterial blood pCO2,
pO2, and pH levels; and antinociception, measured by the tail-flick technique. The administration of 10 mg/kg
(+)-O-desmethyltramadol in a 10-min i.v. infusion
significantly altered pCO2, pO2, and pH values
in comparison with baseline and lower-dose groups
(P < .05). However, 2 mg/kg administered in a
10-min i.v. infusion was enough to achieve 100% antinociception
without respiratory depression. Moreover, the 
-funaltrexamine
pretreatment completely eliminated the antinociception of the 2-mg/kg
dose, suggesting that such an effect is due to µ-opioid receptor
activation. To describe and adequately characterize the in vivo
antinociceptive effect of the drug,
(+)-O-desmethyltramadol was given at different infusion
rates of varying lengths (10-300 min). Pharmacokinetics was best
described by a two-compartmental model. The time course of response was
described using an effect compartment associated with a linear
pharmacodynamic model. The estimates of the slope of the effect versus
concentration relationship were significantly decreased
(P < .05) as the length of infusion was increased,
suggesting the development of tolerance. Doses of up to 8 mg/kg
()-O-desmethyltramadol given in 10-min i.v. infusion
did not elicit either antinociception in the tail-flick test or
respiratory effects. These in vivo results are in accordance with the
opiate and nonopiate properties reported for these compounds in several
in vitro studies.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Tramadol
hydrochloride is a centrally acting analgesic drug that is widely used
in the treatment of pain. It exhibits good analgesic efficacy and a
potency comparable to codeine (Hummel et al., 1996
; Miranda and
Pinardi, 1998).
Tramadol is administered as a racemic mixture of two enantiomers,
(+)-tramadol and ()-tramadol, that are essentially metabolized by the
liver (Lee et al., 1993), producing mainly the
(+)-O-desmethyltramadol, (+)-M1, and
()-O-desmethyltramadol, ()-M1, metabolites,
respectively. There is evidence that the M1 enantiomers show analgesic
activity in mice and rats (Hennies et al., 1988). The fact that these
four compounds [(+)- and ()-tramadol and (+)- and ()-M1] have
different pharmacological properties (Raffa and Friderichs, 1996) makes tramadol an atypical opioid with a complex mechanism of action.
Although the opioid component of tramadol-induced antinociception was
detected in early preclinical in vitro and in vivo studies, the
importance of the nonopioid component has been recognized by Raffa et
al. (1992). Frink et al. (1996) have demonstrated in in vitro receptor
binding and synaptosomal uptake experiments that the (+)-enantiomers
are bound mainly to the opioid receptor, (+)-M1 being the
compound with the highest affinity for the µ-receptors; on the other
hand, ()-enantiomers had the ability to inhibit the noradrenaline
(NA) uptake. Additionally, (+)-tramadol had the property of inhibiting
serotonin uptake. These results have also been supported by other
authors, such as Driessen et al. (1993), Sevcik et al. (1993), Lai et
al. (1996), and Bamigbade et al. (1997).
Although several in vivo studies (Raffa et al., 1992, 1993) dealing
with the role of the opioid and nonopioid components in analgesia
induced by tramadol corroborate the in vitro findings (Raffa et al.,
1995), there is little or no information regarding the
pharmacokinetic (pk) properties of the tramadol enantiomers and their
metabolites or their pharmacokinetic/pharmacodynamic (pk/pd)
relationships. pk/pd studies have been used as a tool for describing
and predicting the time course of the in vivo effect in different
scenarios (Derendorf and Hochhaus, 1995). In the case of tramadol, the
following pk and pd complexities could hamper a priori the
interpretation of the time course of its effect: 1) transport to the
biophase (central nervous system), 2) active metabolites, 3) pd
interactions among the enantiomers and metabolites, and 4) eventual
development of tolerance. For all of these reasons, in this study we
approach the understanding of the in vivo effect of tramadol by
characterizing first the relationship between the pk and the
antinociceptive effects of its metabolites, (+)-M1 and ()-M1. In
addition, the irreversible µ-antagonist -funaltrexamine (-FNA)
was administered to explore the role of µ-receptor in the
antinociception elicited by (+)-M1 because -FNA has been used by
several authors to study the relationship between reduction in
µ-receptor density and loss of agonist efficacy (Adams et al., 1990;
Randich et al., 1993).
When dealing with opioid drugs, it is important to consider their
capability to induce respiratory depression (Lee et al., 1993).
Although tramadol has not caused clinically relevant respiratory depression within the recommended dose range (Houmes et al.,
1992), no studies have been carried out to examine the
respiratory effect of its main metabolites. On the basis of the above
considerations, the respiratory effects of (+)-M1 and ()-M1 were also
evaluated during this study.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Chemicals
The hydrochloride salts of (+)-M1, ()-M1, and the ethoxy
analog of tramadol (used as an analytical internal standard) were kindly supplied by Grünenthal GmbH (Aachen, Germany). -FNA was purchased from Tocris Cookson Ltd. (Bristol, United Kingdom). All
reagents and solvents used were purchased from commercial sources and
were of analytical grade.
Animals
Male Sprague-Dawley rats weighing from 220 to 250 g were used in the experiments. These animals were kept under laboratory standard conditions on a 12-h light/dark cycle, with light from 8:00 AM to 8:00 PM, in a temperature- (21-22°C) and humidity- (70%) controlled room. They were acclimatized for a minimum of 4 days before experiments were performed. Food (Standard Laboratory Rat, Mouse and Hamster diets; Panlab, Barcelona, Spain) and water were available ad libitum. The protocol of the study was approved by the Committee on Animal Experimentation of the University of Basque Country.
Surgical Procedure
The day before the experiment, the rats were lightly anesthetized with diethyl ether (Scharlau, Barcelona, Spain), and two polyethylene catheters (0.5 mm i.d., 11-cm-long; 0.3 mm i.d., 21-cm-long; Vygon, Ecouen, France) were implanted in the left jugular vein and right femoral artery for drug administration and blood sampling, respectively. The catheters were filled with physiological saline solution containing 1% heparin (50 I.U./ml; Roger Lab, Barcelona, Spain) to prevent clotting. These catheters were tunneled under the skin and exteriorized at the dorsal surface of the neck. Animals were housed individually in cages with free access to water.
Drug Analysis
The levels of (+)-M1 and ()-M1 in plasma were determined by
high-performance liquid chromatography with electrochemical detection (Valle et al., 1999). Briefly, plasma samples were spiked with 10 µl
of internal standard followed by 200 µl of ammonium hydroxide. After
the addition of 3 ml of ethyl acetate:N-hexane mixture
(40:60, v/v), samples were shaken on a Vortex mixer for 2 min and
centrifuged for 10 min at 3000 rpm. The organic phase was transferred
to a 5-ml tube and evaporated down at vacuum in an Automatic
Environmental Speed Vac evaporator (AES 100; Savant, Barcelona, Spain).
The dried residues were reconstituted in 100 µl of deionized water, and an aliquot (50 µl) was injected into the chromatographic system.
The chromatographic system consisted of an HPLC 420 pump (Kontron Instruments, Barcelona, Spain) fitted with a manual sample injector (model 7125; Rheodyne, Barcelona, Spain) equipped with a 50-µl loop. Detection was performed with an ESA Coulochem model 5200 (ESA, Bedford, MA) electrochemical detector consisting of a model 5010 dual-electrode analytical cell (ESA) operating in the oxidation screening mode, with the potential of the first electrode set at +610 mV and the second electrode at +875 mV. Owing to the extreme flow sensitivity of the electrochemical detector, a pulse dampener was placed after the pump.
The analytical separation was performed by isocratic separation at room temperature, using an Asahipack ODP-50 column (5-µm particle size, 125- × 4.0-mm i.d.; Hewlett Packard, Palo Alto, CA). The mobile phase, consisting of 0.01 M borate buffer (pH = 9) and methanol (40:60, v/v), was filtered through a 0.22-µm membrane filter (Millipore Corp., Barcelona, Spain) and degassed by sonication. The flow rate was 0.7 ml/min; the mobile phase was recycled to conserve the solvents. The limit of quantification when 100 µl of plasma was used was 10 ng/ml; the signal showed linearity over the range 10 to 4000 ng/ml. The intra- and interday coefficients of variation of the assay were 5.5 and 8.5%, respectively.
(+)-M1 Experiments
Respiratory Depression Studies. Respiratory depression was studied in 20 rats randomly divided into five (n = 4) groups. The control group received a 10-min i.v. infusion of saline solution, and each of the other groups received 10-min i.v. infusions of (+)-M1 with 10, 5, 2.5, or 2 mg/kg, respectively. Arterial blood samples (100 µl) were collected in heparin-washed microtubes just before, during, and after the infusion was stopped at the following times: 0, 10, 15, 20, 25, 30, 40, 55, 70, 85, 100, 130, 160, and 250 min. The pH, pO2, and pCO2 levels were measured immediately by a blood gas analyzer (AVL 990; AVL Biomedical Instruments, Graz, Austria).
pk and Antinociceptive Studies. Animals (n = 33) were randomly divided into seven groups, each receiving a saline solution (three control groups) or a (+)-M1 infusion (groups I-IV) following the schedule represented in Table 1. The choice of the infusion rate for group I was based on the results obtained from the respiratory studies, and it included the highest dose avoiding changes in the respiratory parameters. The infusion rates given to groups II, III, and IV were calculated on the basis of the pk parameters obtained from group I.
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20°C until analysis was performed.
The effects of blood sampling (50-200 µl) and the duration of the
infusion (10-300 min) on the antinociceptive effect were evaluated in
the three control groups receiving saline solution. Antinociception was evaluated with the standard radiant heat
tail-flick technique (D'Amour and Smith, 1941). Tail-flick latency was
measured automatically with an Analgesic-Meter (Letica, Barcelona,
Spain). The intensity of heat was adjusted so that basal latencies were 2 to 3 s; animals with higher baseline (>3-5 s) latencies were excluded from the study. A maximum cut-off time of 10 s was used to avoid tissue damage. Antinociception was expressed as a percentage of maximum possible effect (%MPE) and was calculated using the following expression:
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-FNA Studies.
Male Sprague-Dawley rats (n = 12) were cannulated as described above. Two hours later, when the
rats had recovered from the anesthesia, the antinociceptive baseline
was measured, and a 10-mg/kg bolus dose of -FNA was administered.
Twenty-four hours after -FNA administration, the rats were randomly
divided into two groups receiving either 2 mg/kg (+)-M1 or saline
solution in a 10-min i.v. infusion. Just before, during, and after the
infusions were stopped, antinociception was determined, and arterial
blood samples were withdrawn at the following times: 0, 2.5, 5, 7.5, 10, 12.5, 15, 25, 40, 55, 70, 100, and 130 min. The same volume of
extracted blood was reconstituted with heparinized physiological saline
solution. Blood samples were transferred to heparinized tubes and were
immediately centrifuged at 2500 rpm, 37°C, for 15 min to separate the
plasma. Plasma was frozen and kept at 20°C until analysis was performed.
()-M1 Experiments
pk and Antinociceptive Studies.
Animals (n = 12) were randomly divided into two groups (n = 6). They
received a 2- or 8-mg/kg dose of ()-M1, respectively, in a 10-min
i.v. infusion. Antinociception was determined as previously described
for (+)-M1. Blood samples (50/100/200 µl) were collected at the start
of the infusion and at 2.5, 5, 7.5, 10, 12.5, 15, 20, 30, 40, 55, 70,
90, 120, and 150 min thereafter. In the group receiving the higher
dose, measurements were also performed at 180, 240, and 300 min. Blood
samples were transferred to heparinized tubes and were immediately
centrifuged at 2500 rpm, 37°C, for 15 min to separate the plasma.
Plasma was frozen and kept at 20°C until analysis was performed.
Respiratory Depression Studies.
Animals were randomly
divided into two groups (n = 4) receiving 2 or 8 mg/kg
of ()-M1 in a 10-min i.v. infusion. Arterial blood samples (100 µl)
were collected following the same scheme as described above for (+)-M1;
pH, pO2, and pCO2 levels
were determined.
Data Analysis
The time course of the plasma drug concentrations and
antinociceptive effects was analyzed by population models using the first-order and first-order conditional estimation methods implemented in NONMEM (version V) software (Beal and Sheiner, 1992). This approach makes it possible to fit all data from all individuals simultaneously, describing both mean population tendencies and individual profiles, and providing estimates of the interindividual variability and residual (intraindividual) error. The residual error in
the plasma drug concentrations and antinociceptive effects was
characterized by proportional and additive error models, respectively:
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pkij and pdij, the
residual shift of the observations from the model predictions, are
random variables assumed to be symmetrically distributed around 0 with variances 
2pk and
2pd, respectively. Model
predictions (Cpredij and
Epredij) are based on the pk and pd models
selected (see below) and on the estimates of individual parameters. For
each parameter (P denotes an arbitrary pk or pd parameter),
the expression for the ith individual is:
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i, the shift of the parameter of
the ith individual from the population mean, are
random variables assumed to be symmetrically distributed around 0 with
diagonal variance-covariance matrix 
with diagonal elements
(
12,... , m2). 1... m represent the
pk or pd parameters to which interindividual variability has been
assigned. During the analysis, Ppop, , and 2 were estimated.
pk Analysis.
Multicompartmental pk models were used to
describe the kinetics of both (+)-M1 and ()-M1 in plasma.
Distribution processes were assumed to be linear. In the case of
(+)-M1, a continuous increase in the plasma drug concentrations was
seen during the infusion in group IV, apparently indicating
nonlinearity in the elimination processes. This phenomenon was
empirically modeled as a time-dependent decrease in total plasma
clearance (Cl): Cl = Cl1 · exp(Cl2 · time),
where Cl1 and Cl2 represent
mean population parameters. Elimination of ()-M1 was modeled as a linear process.
pd Analysis.
To model the time course of the response and to
overcome eventual model misspecifications occurring during the pk
analysis, the plasma drug concentration versus time profiles for each
animal were modeled nonparametrically with linear interpolation. When the antinociceptive effect was plotted against the plasma concentration in a time-ordered manner, counterclockwise hysteresis was seen for all
animals. This phenomenon suggests (among other possible explanations) a
time delay for (+)-M1 in plasma to equilibrate with the biophase. Such
a delay has been modeled by linking plasma drug concentrations with
effect site concentrations (Ce) by
means of a first-order rate constant
(ke0; Sheiner et al., 1979). Linear, Emax, and
sigmoidal Emax models were explored to
describe the pd (effect versus Ce)
relationship. This analysis shows that the pd parameters of (+)-M1
depended on the length of the infusion, which could be interpreted as a
development of tolerance. Therefore, models accounting for tolerance
development (Porchet et al., 1988; Ekblom et al., 1993; Mandema and
Wada, 1995) were also fitted to the data.
), the estimates of the parameters, and their confidence intervals. The minimum value of the objective function provided by NONMEM was also used as a criterion for model selection. The difference in the objective function between two hierarchical models is
approximately 
2 distributed; P < .05 was used as the level of significance. Results from the data
analysis are presented as estimated values and their coefficients of
variation [c.v. (%)]. Estimates of the interindividual and
residual variability are expressed as c.v. (%).
Statistical Analysis
Results from the respiratory effects and antinociception for the
-FNA experiments were represented as mean data with their corresponding standard deviations. Comparisons among groups were made
by one-way ANOVA followed by the Scheffe's F test.
Statistical significance was set at P < .05.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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(+)-M1 Experiments
Respiratory Depression.
(+)-M1, administered as an i.v.
infusion for 10 min, elicited a dose-dependent respiratory depression
characterized by a decrease in the arterial pH and
pO2 and an increase in arterial
pCO2 levels (Fig.
1). Although the pH levels decreased from
a mean baseline value of 7.5 to minimum values of 7.43, 7.39, 7.37, and
7.22 after the administration of the 2-, 2.5-, 5-, and 10-mg/kg dose,
respectively, only the decrease observed after the highest dose was
found to be statistically significant (P < .05).
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pk.
The mean observed plasma concentrations of (+)-M1 versus
time profiles for groups I to IV are represented in Fig.
2. Maximum mean observed plasma drug
concentrations were 639.2 ± 299.6, 187.54 ± 79.5, 208.62 ± 36.7, and 261.4 ± 37.2 ng/ml for groups I to IV,
respectively.
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pk/pd Analysis of the Antinociceptive Effect. When saline was administered in infusions of 10, 60, or 300 min, no antinociception was observed. The %MPE ranged between 0 and 29%. Baseline antinociceptive measurements did not differ statistically (P > .05) between control and drug-treated groups.
The time course of the antinociception in groups I to IV is shown in Fig. 3. The mean peak observed effect in groups I and III was 100%. For groups II and IV, the maximum observed effect was 42.9 and 90.5%, respectively. Time to peak was 15 min for groups I and II. Time to peak for groups III and IV occurred at the end of the infusion (60 and 300 min, respectively).
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-FNA Experiments.
The pretreatment with 10 mg/kg -FNA
did not alter the baseline antinociception; however, as is represented
in Fig. 4, -FNA pretreatment
antagonized completely the antinociceptive effect of the 2-mg/kg dose
of (+)-M1 administered in a 10-min i.v. infusion, the maximum mean
observed effect being 11.7%. pk parameters of (+)-M1 in rats
pretreated with -FNA did not differ (P > .05) from
those obtained for groups I to IV (data not shown).
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()-M1 Experiments
Figure 5 shows the pk profiles of
()-M1 after the administration of a 2- or 8-mg/kg dose in 10-min i.v.
infusions. The disposition of ()-M1 in plasma was best described by a
two-compartmental model. pk behavior was different between the two
administered dose groups. Differences affected initial volume of
distribution and total plasma clearance. Table
4 lists the estimates of the pk
parameters.
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Antinociceptive and respiratory measurements were recorded during and
after the infusion of ()-M1. However, no significant changes
(P > .05) from baseline were detected in either effect (data not shown).
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Tramadol is a centrally acting analgesic drug with several
potentially complicating pk/pd factors that could make the
interpretation of the time course of antinociception difficult. In
fact, to our knowledge nothing describing its pk/pd relationships has
been published. These factors include: 1) Kinetic disequilibrium
between plasma and biophase (central nervous system). Several authors have reported delays between plasma and the effect compartment for
several opioid drugs, such as morphine (Ekblom et al., 1993), methadone
(Garrido et al., 1999), and alfentanyl (Mandema and Wada, 1995). 2)
Tolerance development. This phenomenon has also been observed and
quantified for opioid drugs such as morphine (Ouellet and Pollack,
1995, Gårdmark et al., 1993) and alfentanyl (Mandema and Wada, 1995).
3) Pharmacodynamic interactions. Tramadol is administered as a racemic
mixture of two active enantiomers (Raffa et al., 1993), and,
consequently, interactions are expected to be present. In addition,
each of the enantiomers forms active metabolites (Paar et al., 1992)
that could modify these interactions or make them more complex.
The aim of this work is the analysis of the pk/pd relationships of the
two main active metabolites, (+)-M1 and ()-M1, because there are some
indications that suggest they might play a significant role in the
analgesic effect of tramadol (Raffa and Friderichs, 1996). Both
metabolites were administered separately because this type of design
offers the advantage of obtaining direct information about the pk and
pd properties of the metabolites, and this design has been
previously used for other drugs with active metabolites like midazolam
(Mandema et al., 1992).
(+)-M1 Experiments.
(+)-M1 was administered at different rates
in i.v. infusions of different lengths. This procedure is similar to
that used by Gårdmark et al. (1993) to evaluate the pk/pd properties
of morphine. The tail-flick test has been shown to be appropriate for
characterizing in vivo responses associated with the interaction of
agonists with the µ-receptor, as has been reported for buprenorphine (Ohtani et al., 1995), methadone (Garrido et al., 1999), and morphine (Ouellet and Pollack, 1997).
) or to 3 mg/kg
norbuprenorphine (active metabolite of buprenorhine) administered as an
i.v. bolus (Ohtani et al., 1997).
(+)-M1 kinetics in plasma was best described with a two-compartmental
model. The distribution phase was fast (distribution half-life = 1.2 min) and linear over the dose range studied. However, clearance
showed a slight decrease in time after the start of the
infusion. A similar pattern has been described previously for
other opioids administered in long infusions. Ekblom et al. (1993) and
Gårdmark et al. (1993) observed that total plasma clearance of
morphine decreased after long infusions when compared with those
estimated from short infusions or bolus data. In our study, because
maximum plasma drug concentrations were similar for groups II, III, and
IV, the decrease in clearance could not be explained by a
concentration-dependent process. This finding could be related to the
fact that there is a possibility for higher respiratory effects during
the 300-min infusion than during the 10- or 60-min infusions; however,
the effect of respiratory depression on the elimination of (+)-M1 has
not been established yet.
The 20-min estimate of the mean population terminal half-life obtained
in this study differs from the 4.23-h estimate reported previously by
Takacs (1995). Because the administered drug was tramadol in that
study, those differences suggest that the rate of elimination of (+)-M1
is limited by its rate of formation from the parent compound.
The pk/pd analysis of the antinociceptive effect suggests tolerance
development because the estimates of
ke0 and slope increase and decrease,
respectively, with the length of the infusion (Table 3). In addition,
for the two 10-min infusions, the one associated with higher plasma
drug concentrations (group I) corresponds to a higher
ke0 and lower slope values. These
results indicate that development of tolerance depends on total drug
exposure. Although a priori, our experimental design was appropriate to
account for development of tolerance, owing to the fact that during the
longer infusion plasma drug concentrations were continuously
increasing, such a phenomenon could not be adequately quantified.
The value of mean population estimates of
ke0 (0.03/min) for the 10-min lowest
dose infusion group (no, or minor tolerance development) was lower than
the value estimated for methadone (1.44/min; Garrido et al., 1999),
similar to that estimated for morphine (0.073/min; Ouellet and Pollack,
1995), and higher than those described for morphine-6-glucuronide
(0.005/min; Gårdmark and Hammarlund-Udenaes, 1998) and morphine
(0.02/min; Gårdmark et al., 1993). These differences could be
explained by differences in liposolubility between the drugs (Dutta et
al., 1998).
Recently, Grond et al. (1999) determined the plasma concentrations of
the enantiomers of tramadol and M1 metabolite following an i.v. bolus
dose of 200 mg and demand doses of 20 mg. It was found that the mean
(+)-M1 plasma drug concentration before demand was 57 ng/ml, so (+)-M1
plasma concentrations were probably well above 57 ng/ml at times near
drug administration. Taking into account that our experiments showed
that (+)-M1 steady-state plasma drug concentrations of 200 ng/ml elicit
near maximal antinociception, (+)-M1 could be expected to have a role
in the analgesic effect of tramadol. However, additional studies
are required to characterize the nature of the tramadol/(+)-M1
interaction in humans.
-FNA is a µ-selective irreversible antagonist that produces a
long-lasting antagonism of several behavioral effects of µ-agonist. However, it does not antagonize the effects of drugs acting at 
- or
-opioid receptors (Pitts et al., 1998). Generally, the antagonism of
-FNA evidences the fact that a given behavioral effect of a drug
involves actions on µ-opioid receptors. The insurmountable antagonism
of -FNA on the antinociceptive effect elicited by (+)-M1 supports
the results from in vitro studies where (+)-M1 showed a moderate
affinity for µ-opioid receptors: Ki = 153 nM (Lai et al., 1996), and shows that the behavior of (+)-M1 in
the antinociceptive test is mediated by µ-opioid receptors. Similar results were reported by Randich et al. (1993) for a 1-mg/kg i.v. dose
of morphine given 24 h after pretreatment with a 10-mg/kg i.v.
bolus of -FNA in rats, using the tail-flick reflex test.
()-M1 Experiments.
The kinetics of ()-M1 was best
described using a two-compartmental model. The 4-fold differences found
in total clearance and initial volume of distribution between the two
doses used in the current study could explain dose-dependent
distribution and elimination kinetics. The pk estimates obtained from
the analysis of the lower-dose group were similar to those obtained
during the pk analysis of the (+)-M1 data, suggesting that, after
administration of low doses, both enantiomers have similar kinetics.
)-M1 presents a very low affinity for opioid receptors (Lai et al.,
1996), its main action being due to the inhibition of the NA uptake
(Driessen et al., 1993). As was expected on the basis of the in vitro
properties of ()-M1, no antinociceptive effect in the tail-flick test
or respiratory depression was observed after the administration of this
compound in this study, despite the high administered doses.
Several in vivo studies have reported an important contribution by the
nonopiate component of tramadol in its antinociception because a
peripheral administration of the
alpha2-adrenergic antagonists, such as yohimbine,
blocked partially its antinociceptive effect (Raffa et al., 1995). In addition, the potentiation of opioid analgesia by NA uptake blockers and 
2-agonists is documented in clinical and
preclinical findings, although there is no consensus about the
intrinsic antinociceptive effect of these compounds on their own
(Sevcik et al., 1993; Codd et al., 1995). In this case, the ()-M1, a
compound with the property to inhibit NA uptake, did not induce either
antinociceptive effect in the tail-flick test or adverse effects such
as respiratory depression.
In conclusion, this study represents the first pk/pd analysis of the
two main active metabolites of tramadol. The pharmacokinetics of both
compounds can be considered similar and is well described with
multicompartmental models. Antinociceptive response elicited by (+)-M1
could be described by standard pk/pd models and was mediated by
µ-opioid receptor activation. In our results we found evidence for
the development of tolerance. Respiratory effects were observed at
higher doses than the ones given the maximum antinociception. ()-M1
showed neither antinociception in the tail-flick test nor respiratory
effects. Further studies are required to account for the interaction of
both compounds given simultaneously.
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Acknowledgments |
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We thank Professor José M. Baeyens for critical review of
the pharmacodynamic concepts and Professors Mats O. Karlsson and Margareta Hammarlund-Udenaes for suggestions regarding the
pharmacokinetic/pharmacodynamic data analysis. The generous gift of
(+)-O-desmethyltramadol,
()-O-desmethyltramadol, and ethoxy analog of tramadol by
Grünenthal GmbH is greatly appreciated.
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Footnotes |
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Accepted for publication January 31, 2000.
Received for publication August 31, 1999.
1 This work was supported by a grant from the University of Basque Country (026, EB 231/96). M.V. was supported by a fellowship from the University of Basque Country.
2 Current address: Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, CA.
3 Current address: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, Pamplona, Spain.
Send reprint requests to: Iñaki F. Trocóniz PhD, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, Pamplona 31080, Spain. E-mail: itroconiz{at}unav.es.
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Abbreviations |
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%MPE, percentage of maximum possible effect;
M1, O-desmethyltramadol;
-FNA, -funaltrexamine;
pk, pharmacokinetic;
pd, pharmacodynamic;
NA, noradrenaline;
Cl, total
plasma clearance;
c.v., coefficients of variation.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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-funaltrexamine.
J Pharmacol Exp Ther
255:
1027-1032-hydroxymidazolam in healthy volunteers.
Clin Pharmacol Ther
51:
715-728[Medline].This article has been cited by other articles:
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M. J. Garrido, M. Valle, M. A. Campanero, R. Calvo, and I. F. Trocóniz Modeling of the In Vivo Antinociceptive Interaction between an Opioid Agonist, (+)-O-Desmethyltramadol, and a Monoamine Reuptake Inhibitor, (-)-O-Desmethyltramadol, in Rats J. Pharmacol. Exp. Ther., October 1, 2000; 295(1): 352 - 359. [Abstract] [Full Text]
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), 10 (
), 5 (
), or 2.5 (
) mg/kg (+)-M1 in 10-min i.v. infusions. Points represent the mean
data and vertical lines represent the standard deviations.
). Lines represent mean population model predictions
for groups I (
