Pharmacokinetics of Tramadol and its Three Main Metabolites in Healthy Male and Female Volunteers
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BIOPHARMACEUTICS & DRUG DISPOSITION
Biopharm. Drug Dispos. 28: 526–533 (2007)
Published online in Wiley InterScience
(www.interscience.wiley.com) DOI: 10.1002/bdd.584
Pharmacokinetics of Tramadol and its Three Main Metabolites
in Healthy Male and Female Volunteers
Yalda H. Ardakani and Mohammad-Reza Rouini*
Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences,
14155-6451, Tehran, Iran
ABSTRACT: By using a high-performance liquid chromatography method, the pharmacokinetics
of the tramadol (T) and its three main metabolites, O-desmethyltramadol (M1), N-desmethyl-
tramadol (M2) and O,N-didesmethyltramadol (M5) was studied in healthy male and female Iranian
volunteers after oral administration of two 50 mg tramadol hydrochloride tablets. The related
pharmacokinetic parameters such as Cmax, Tmax, AUC(0–t), AUC(0–1), T1/2 and Cl/F were calculated
and compared between the two genders. No significant differences were found in the systemic
exposure and pharmacokinetic of tramadol, M1 and M2 while there were significant differences in
AUCs of M5 in the two genders. It was concluded that to get a more accurate result, the gender
dependency of T and its metabolites might be studied in specific phenotypes. Copyright # 2007
John Wiley & Sons, Ltd.
Key words: tramadol; O-desmethyltramadol; N-desmethyltramadol; O,N-didesmethyltramadol;
pharmacokinetics
Introduction Pharmacokinetic studies have shown that
tramadol is rapidly and almost completely
Tramadol hydrochloride (T) is a synthetic opioid absorbed after an oral administration. However,
analgesic of the amino-cyclohexanol type that has its mean absolute bioavailability is only 65–70%
two chiral centers. The marketed drug is the due to the first-pass hepatic metabolism [3]. The
racemate of the trans isomers. It has an analgesic peak plasma concentration is reached in 1–3 h
efficacy and potency ranging between weak after oral administration and following a single
opioids and morphine [1]. oral dose of 100 mg, Cmax is approximately
Two synergistic mechanisms of action are 300 ng/ml [4]. Tramadol is rapidly distributed
responsible for its analgesic activity, as tramadol in the body, with a distribution half-life in the
is both an opioid agonist with selectivity for the initial phase of 6 min, followed by a slower
m-receptor and an inhibitor of monoamine neu- distribution phase with a half-life of 1.7 h. The
rotransmitter (noradrenaline and serotonin) re- high total distribution volume of 306 liters after
uptake. This dual mechanism of action may be oral administration indicates high tissue affinity;
attributed to the differences between the two the plasma protein binding is about 20% [5].
enantiomers of racemic tramadol [2]. This analgesic is rapidly and extensively
metabolized in the liver. The principal metabolic
pathways, O- and N-desmethylation, involve
*Correspondence to: Biopharmaceutics and Pharmacokinetic cytochrome P-450 isoenzymes 2D6, 2B6 and
Division, Department of Pharmaceutics, Faculty of Pharmacy,
Tehran University of Medical Sciences, 14155-6451, Tehran, Iran. 3A4, respectively [4]. The primary metabolites
E-mail: rouini@tums.ac.ir O-desmethyltramadol (M1) and N-desmethyltra-
Received 3 May 2007
Revised 18 July 2007
Copyright # 2007 John Wiley & Sons, Ltd. Accepted 18 July 2007PHARMACOKINETICS OF TRAMADOL 527
madol (M2) may be further metabolized to 28 l/h) and 710–742 ml/min (approximately 43–
three additional secondary metabolites namely, 44 l/h) following intravenous and oral adminis-
N,N-didesmethyltramadol (M3), N,N,O-trides- tration, respectively, with a mean elimination
methyltramadol (M4) and N,O-didesmethyltra- half-life of about 5–7 h [3].
madol (M5). In phase II, the O-demethylated Only one of these metabolites, O-desmethyl-
metabolites are conjugated with glucuronic tramadol (M1), is pharmacologically active. After
acid and sulfuric acid before excretion into urine. oral administration of 100 mg tramadol, the Tmax
In all species, M1 and M1 conjugates, M5 and of M1 is about 1.4 h longer than that of tramadol
M5 conjugates, and M2 are the main metabolites, with the Cmax of no more than 18–26% of the
whereas M3, M4 and M4 conjugates are parent drug. After multiple oral doses or admin-
only formed in minor quantities (less than istration of SR capsules, the time to reach Cmax for
1%) (Figure 1). Approximately 10–30% of tramadol and M1 was similar [8]. Up to now, the
the parent drug is excreted unchanged in gender dependency of pharmacokinetics of tra-
the urine. Like tramadol, all metabolites are madol and its main metabolites has not been
almost completely excreted via the kidney; investigated in detail. Liu et al. showed that there
from a quantitative point of view, biliary excre- is a gender related difference in the systemic
tion of these components is negligible [6]. In exposure and related pharmacokinetic para-
a study where a 50 mg oral dose of tramadol meters of both enantiomers of tramadol and M1
was given to 104 volunteers, mean values for in Chinese volunteers [9].
tramadol, M1 and M2 excretion in 24 h urine The purpose of this study was to investigate in
were 12%, 15% and 4% of the administered dose, detail the nonstereoselective pharmacokinetic of
respectively [7]. tramadol and its main three metabolites follow-
The mean total clearance of tramadol has been ing a 100 mg single oral dose in Iranian male and
reported to be about 467 ml/min (approximately female healthy volunteer groups.
T
M2
M1
M1 conjugates M5
M3
M5 conjugates
M4
Figure 1. Metabolic pathway of tramadol
Copyright # 2007 John Wiley & Sons, Ltd. Biopharm. Drug Dispos. 28: 526–533 (2007)
DOI: 10.1002/bdd528 Y.H. ARDAKANI AND M.-R. ROUINI
Material and Methods Sample collection
Blood samples (3 ml) were collected in hepar-
Chemicals and reagents
inized glass tubes before (time 0) and 0.5, 1, 1.5, 2,
The pure substances of tramadol, M1, M2, M5 2.5, 3.5, 4.5, 6, 8, 10 and 24 h after administration.
and cis-tramadol as internal standard were Plasma was harvested after separation from
kindly supplied by Grünenthal (Stolberg, Ger- blood cells by centrifugation and stored at
many). HPLC-grade acetonitrile and methanol 208C until analysis.
and analytical grade ethyl acetate and phospho-
ric acid (85%) were supplied by Merck (Darm- Analytical method
stadt, Germany).
The tramadol, M1, M2 and M5 in plasma were
determined by a previously described HPLC
Subjects method [10] with minor modification made to
improve the efficiency of the method. Briefly, all
Twenty four healthy Iranian volunteers (12 male analytes were extracted with ethylacetate and
and 12 female) met the entry requirements and injected to a chromatographic system consisted
completed the study. The mean demographic of a low-pressure gradient HPLC pump, a
data of age, height and weight of volunteers are fluorescence detector [excitation wavelength
shown in Table 1. (lex) 200 nm/emission wavelength (lem) 301 nm]
None of the participants had any significant and an online degasser, all from Knauer (Berlin,
diseases, as determined by their medical Germany). Separation was achieved by a Chro-
history, physical examination and routine labora- molithTM Performance RP-18e 100 mm 4.6 mm
tory tests and they were negative for hepatitis B column (Merck, Darmastadt, Germany) pro-
antigen. All subjects were informed about tected by a ChromolithTM guard cartridge RP-
the aim and risks of the study by the clinical 18e 5 mm 4.6 mm. A mixture of methanol:
investigator, based on a written informed con- water (19:81, v/v) adjusted to pH 2.5 by
sent. The protocol was approved by the Ethics phosphoric acid at flow rate of 2 ml/min was
Committee of Tehran University of Medical used as mobile phase. The data were acquired
Sciences. and processed by means of ChromGate chroma-
Subjects were not allowed to take any tography software (Knauer, Berlin, Germany).
other medication for 2 weeks before and through-
out the study. Each subject fasted for 12 h
Pharmacokinetic calculation
before administration of two 50 mg tramadol
tablets (Grünenthal) with 200 ml of water. The The pharmacokinetics of tramadol and its meta-
subjects continued to fast for 3 h after adminis- bolites were determined by noncompartmental
tration. Standard breakfast and lunch were analysis. The maximum plasma concentrations
served 3 h and 6 h after dosing, respectively. (Cmax) and their corresponding times (Tmax) were
The subjects remained under close medical recorded as observed. The elimination rate
supervision until 10 h after the collection of the constant (b) was estimated as the absolute value
last blood samples. of the slope of a least-square linear regression
Table 1. Mean demographic data for subjects (n ¼ 12)
Male Female
Age (year) Weight (kg) Height (cm) Age (year) Weight (kg) Height (cm)
Mean 27.8 73.9 173.4 35.3 69.9 160.1
SD 7.0 10.2 4.4 6.3 10.3 10.4
Min 22 60 165 23 55 150
Max 42 80 180 42 85 165
Copyright # 2007 John Wiley & Sons, Ltd. Biopharm. Drug Dispos. 28: 526–533 (2007)
DOI: 10.1002/bddPHARMACOKINETICS OF TRAMADOL 529
of the terminal phase of the logarithmic plasma the peak area ratios against the corresponding
concentration–time curve. The plasma terminal concentrations in standard plasma samples. The
half-life (t1/2) was calculated as 0.693/b. The area calibration curves were constructed over concen-
under the plasma concentration–time curve trations in the range 5–500 ng/ml for all analytes.
(AUC0–t) from time zero to the time of The intraassay accuracy was acceptable and for
last quantifiable concentration (Ct) was calcu- the mean concentration of standard replicates did
lated using the linear trapezoidal method. not exceed 107.1% of the normal concentration.
The area under the plasma concentration–time The intraassay precision, defined as the coeffi-
curve from time zero to the infinite time cient of variation (n ¼ 5) calculated in the
(AUC0–1) was calculated as the sum of corre- determination of accuracy, was acceptable and
sponding AUC0–t and Ct/b values. The plasma was less than 10.5%.
oral clearance (CL/F) was calculated as Dose/
AUC0–1. The apparent volume of distribution Pharmacokinetics of tramadol
(Vd/F) was determined using the equation Vd =F
¼ ðDose=AUC021 Þ=b. The mean plasma concentration–time curves of
tramadol in the healthy male and female volun-
Statistical evaluation teers are depicted in Figure 3 and the corre-
sponding pharmacokinetic variables are
Data are expressed as mean SD. To compare summarized in Table 2.
the pharmacokinetic parameters of tramadol and The maximum concentration of tramadol in
its metabolites in males and females, an unpaired the plasma occurred at 1.5 h after administration
t-test was used for all parameters except Tmax, in male subjects and after 1.8 h in female subjects
with which a nonparametric Wilcoxon two- in approximately the same amount in both
sample test was used. The significance limit genders. There was no significant difference in
accepted for all statistical analyses was set at all calculated pharmacokinetic parameters be-
a ¼ 0:05. tween the male and female subjects (p>0.05).
Pharmacokinetics of O-desmethyltramadol (M1)
Results
Mean plasma concentration–time curves of M1 in
Chromatography both sexes are shown in Figure 4 and the related
pharmacokinetic parameters are reviewed in
Under the analytical condition mentioned above, Table 3.
tramadol, its metabolites and IS (Internal Stan- The time to reach the maximum plasma
dard) were well separated and there was no concentration of M1 took place approximately
interference from human plasma (Figure 2). The
calibration curves were constructed by plotting 450
400 Male
350 Female
C 300
Conc. (ng/ml)
Is
M1 M5 T M2 250
B 200
150
A
100
1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 50
Minutes
0
0 5 10 15 20 25
Figure 2. Chromatograms of tramadol and its metabolites (T), Time (h)
(M1), (M2), (M5) and cis-tramadol (IS) in human plasma. (A)
Blank human plasma spiked with Is; (B) Plasma spiked with Figure 3. Mean plasma concentration–time curves of trama-
T, M1, M2, M5 and IS; (C) Plasma of a volunteer 2 h after dol in the healthy male and female Iranian subjects after a
single oral administration of 100 mg tramadol single oral dose of two 50 mg tramadol tablets
Copyright # 2007 John Wiley & Sons, Ltd. Biopharm. Drug Dispos. 28: 526–533 (2007)
DOI: 10.1002/bdd530 Y.H. ARDAKANI AND M.-R. ROUINI
Table 2. Pharmacokinetic parameters of tramadol in healthy male and female subjects after a single oral dose of two 50 mg
tramadol tablets
Parameter Tramadol
Male Female p value (before exclusion) p value (after exclusion)
Cmax (ng/ml) 337.4 60.8 314.4 53.3 0.92 0.91
Tmax (h) 1.5 0.5 1.8 0.4 0.31 0.34
AUC(0–t) (ng/ml/h) 2381.8 490.3 2622.2 523.1 0.26 0.27
AUC(0–1) (ng/ml/h) 2607.5 528.6 3017.4 699.3 0.17 0.18
T1/2 (h) 7.0 1.0 7.1 0.4 0.94 0.67
CL/F (ml/min) 664 135 592 116 0.42 0.43
Vd/F (1) 374 82 384 63 0.39 0.42
n ¼ 12, mean SD.
Table 3. Pharmacokinetic parameters of M1 in healthy male and female volunteers
Parameter O-desmethyltramadol (M1)
Male Female p value (before exclusion) p value (after exclusion)
Cmax (ng/ml) 88.8 35.9 88.6 23.7 0.99 0.73
Tmax (h) 2.3 0.8 2.4 0.7 0.96 0.40
AUC(0–t) (ng/ml/h) 904.2 265.5 959.6 252.7 0.61 0.77
AUC(0–1) (ng/ml/h) 1034.5 304.7 1165.4 318.4 0.31 0.39
T1/2 (h) 7.9 1.6 7.4 1.1 0.48 0.23
n ¼ 12, mean SD.
120 difference in all calculated parameters between
100
Male the sexes.
Female
80
Conc. (ng/ml)
Pharmacokinetics of N-desmethyltramadol (M2)
60
The plasma concentration profiles of M2 in both
40 male and female volunteers are depicted in
20
Figure 5 and their pharmacokinetic parameters
are calculated and summarized in Table 4.
0
0 5 10 15 20 25
The time to reach the maximum plasma
Time (h) concentration of M2 occurred approximately
in the same time in both sexes. The values of
Figure 4. Mean plasma concentration–time curves of M1 in
the healthy male and female Iranian volunteers after a single Cmax were higher (25%) in the females than in
oral dose of two 50 mg tramadol tablets males and the values of AUC0–t and AUC0–1
were higher (40%) and (50%) in female
than in male volunteers, respectively. Although
the systemic exposure of females was higher
1 h after tramadol Tmax. The maximum plasma (25–50%) than male volunteers, the difference
concentration of M1 reached about 25% of between corresponding parameters was not
tramadol corresponding parameter. statistically significant.
The area under the plasma concentration–time The Cmax and AUCs of M2 were about (5–
curve of M1 was approximately (32–35%) of the 18%) and (5–35%) of related parameters of
same parameter in tramadol in both genders. As tramadol in females and (4–12%) and (4–
mentioned in Table 3, there was no significant 20%) in males, respectively.
Copyright # 2007 John Wiley & Sons, Ltd. Biopharm. Drug Dispos. 28: 526–533 (2007)
DOI: 10.1002/bddPHARMACOKINETICS OF TRAMADOL 531
Pharmacokinetics of O, N-didesmethyltramadol CYP2D6 and MDR1 polymorphism [11,12]. In
(M5) addition, the biotransformation of tramadol varies
within the population of the EM phenotype based
Figure 6 shows the mean plasma concentration–
on the number of functional CYP2D6 alleles [13].
time curves of M5 in both sexes. The correspond-
It has been stated that CYP2D6 activity may be
ing pharmacokinetic parameters are reviewed in
higher in males than in females [14]. By contrast
Table 5.
Liu et al. found a higher rate of O-demethylation
The Tmax of M5 were approximately the same
of tramadol mediated by CYP2D6 resulting in
in both genders but the values of Cmax, AUC0–t
higher Cmax and AUC of the metabolite (M1) in
and AUC0–1 were higher about 25%, 35% and
females than in males [9]. However, the results
45% in females than in males, respectively. The
obtained in our study did not show a significant
differences between Cmax, Tmax and T1/2 were not
difference in non-stereoselective pharmacoki-
statistically significant while AUCs were statisti-
netic parameters of T and M1 between the two
cally different from each other.
genders in our volunteers. This finding is in
The Cmax and AUCs of M5 were about 3–16%
concordance with the results of the study of May
and 5–28% of that of the parent compound in
et al. that debrisoquine 4-hydroxylation is not
females and 5–14% and 6–19% in males,
influenced by gender [15].
respectively.
As shown in Figure 1, the M5 metabolite may
be formed either by N-demethylation of M1
mediated mainly by CYP3A4 or O-demethylation
Discussion of M2 mediated by 2D6.
The high variability in the pharmacokinetic
properties of tramadol has been related partly to
60 60
Male Male
50 Female 50 Female
40
Conc, (ng/ml)
40
Conc. (ng/ml)
30 30
20 20
10 10
0 0
0 5 10 15 20 25 0 5 10 15 20 25
Time (h) Time (h)
Figure 5. Mean plasma concentration–time curves of M2 in Figure 6. Mean plasma concentration–time curves of M5 in
the healthy male and female Iranian volunteers after a single the healthy male and female Iranian volunteers after a single
oral dose of two 50 mg tramadol tablets oral dose of two 50 mg tramadol tablets
Table 4. Pharmacokinetic parameters of M2 in healthy male and female volunteers
Parameter N-desmethyltramadol (M2)
Male Female p value (before exclusion) p value (after exclusion)
Cmax (ng/ml) 24.8 15.1 33.4 22.2 0.27 0.13
Tmax (h) 2.8 1.1 2.8 0.9 0.93 0.47
AUC(0–t) (ng/ml/h) 253.2 186.7 421.1 352.7 0.21 0.12
AUC(0–1) (ng/ml/h) 334.8 292.8 750.3 518.4 0.22 0.13
T1/2 (h) 10.3 2 10.8 2.5 0.26 0.38
n ¼ 12, mean SD.
Copyright # 2007 John Wiley & Sons, Ltd. Biopharm. Drug Dispos. 28: 526–533 (2007)
DOI: 10.1002/bdd532 Y.H. ARDAKANI AND M.-R. ROUINI
A metabolic switch in favor of enhanced N- comparison of pharmacokinetic parameters of
demethylation of T has been suggested in the M2 in male and female subjects. The pharmaco-
presence of low CYP2D6 activity in the PM kinetic parameters of M5 were also compared in
phenotype population [13]. This metabolic switch both groups (Table 5) and no significant differ-
may lead to an increase in the M2 concentration ence was obtained for Cmax, Tmax and T1/2.
level. Despite the presence of more substrate However, AUC(0–t) and AUC(0–1) were signifi-
(M2) available for M5 formation, less M5 may be cantly different in the two groups.
formed as a result of decreased O-demethylation As shown in Figure 7, subject 4 from the female
of M2 by 2D6. According to the results listed in group and subjects 11 and 12 from the male
Table 4, no significant difference was detected in group were different from the other subjects in
Table 5. Pharmacokinetic parameters of M5 in healthy male and female volunteers
Parameter O,N-didesmethyltramadol (M5)
Male Female p value (before exclusion) p value (after exclusion)
Cmax (ng/ml) 26.3 11.7 34.4 10.4 0.09 0.04
Tmax (h) 2.6 1.2 2.8 1.7 0.75 0.57
AUC(0–t) (ng/ml/h) 264.5 99.8 394.7 153.4 0.02 0.01
AUC(0–1) (ng/ml/h) 327.2 101.6 584.7 267.7 0.004 0.002
T1/2 (h) 9.1 2.8 8.7 2.7 0.76 0.78
n ¼ 12, mean SD.
0.70
AUC ratio (metabolite/tramado)
0.60 Female M1 M2 M5
0.50
0.40
0.30
0.20
0.10
0.00
1 2 3 4 5 6 7 8 9 10 11 12
Volunteers
0.7
AUC ratio (metabolite/tramado)
0.6 Male M1 M2 M5
0.5
0.4
0.3
0.2
0.1
0.0
1 2 3 4 5 6 7 8 9 10 11 12
Volunteers
Figure 7. The AUC0–1 ratio (metabolite/tramadol) for M1, M2 and M5 in both genders
Copyright # 2007 John Wiley & Sons, Ltd. Biopharm. Drug Dispos. 28: 526–533 (2007)
DOI: 10.1002/bddPHARMACOKINETICS OF TRAMADOL 533
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