Pharmacokinetics of tramadol after subcutaneous administration in a critically ill population and in a healthy cohort (original) (raw)
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Comparative bioequivalence studies of tramadol hydrochloride sustained-release 200 mg tablets
2010
Background: Tramadol hydrochloride is available as 50 mg immediate-release (IR) and 100 mg, 200 mg, and 300 mg sustained-release (SR) tablets. The recommended dose of tramadol is 50-100 mg IR tablets every 4-6 hours. The tramadol SR 200 mg tablet is a better therapeutic option, with a reduced frequency of dosing, and improved patient compliance and quality of life. The present study evaluated the bioequivalence of a generic tramadol SR 200 mg tablet. Methods: A comparative in vitro dissolution study was performed on the test and reference products, followed by two separate single-dose bioequivalence studies under fasting and fed conditions and one multiple-dose bioequivalence study under fasting conditions. These bioequivalence studies were conducted in healthy human subjects using an open-label, randomized, two-treatment, two-period, two-sequence, crossover design. The oral administration of the test and reference products was done on day 1 for both the single-dose studies and on days 1-5 for the multiple-dose study in each study period as per the randomization code. Serial blood samples were collected at predefined time points in all the studies. Analysis of plasma concentrations of tramadol and O-desmethyltramadol (the M 1 metabolite) was done by a validated liquid chromatography-mass spectrometry analytical method. The standard acceptance criterion of bioequivalence was applied on log-transformed pharmacokinetic parameters for tramadol and its M 1 metabolite. Results: The ratios for geometric least-square means and 90% confidence intervals were within the acceptance range of 80%-125% for log-transformed primary pharmacokinetic parameters for tramadol and its M 1 metabolite in all the three studies. Conclusion: The test product is bioequivalent to the reference product in terms of rate and extent of absorption, as evident from the single-dose and multiple-dose studies. Both the treatments were well tolerated.
European Journal of Pharmaceutical Sciences, 2016
Tramadol hydrochloride is a centrally acting analgesic used for the treatment of moderate-to-severe pain. It has three main metabolites: O-desmethyltramadol (M1), N-desmethyltramadol (M2), and N,O-didesmethyltramadol (M5). Because of the frequent use of tramadol by patients and drug abusers, the ability to determine the parent drug and its metabolites in plasma and cerebrospinal fluid is of great importance. In the present study, a pharmacokinetic approach was applied using two groups of five male Wistar rats administered a 20 mg/kg dose of tramadol via intravenous (i.v.) or intraperitoneal (i.p.) routes. Plasma and CSF samples were collected at 5-360 min following tramadol administration. Our results demonstrate that the plasma values of C max (C 0 in i.v. group) and area under the curve (AUC) 0-t for tramadol were 23,314.40 ± 6944.85 vs. 3187.39 ± 760.25 ng/mL (C max) and 871.15 ± 165.98 vs. 414.04 ± 149.25 μg•min/mL in the i.v. and i.p. groups, respectively (p b 0.05). However, there were no significant differences between i.v. and i.p. plasma values for tramadol metabolites (p N 0.05). Tramadol rapidly penetrated the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) (5.00 ± 0.00 vs. 10.00 ± 5.77 min in i.v. and i.p. groups, respectively). Tramadol and its metabolites (M1 and M2) were present to a lesser extent in the cerebrospinal fluid (CSF) than in the plasma. M5 hardly penetrated the CSF, owing to its high polarity. There was no significant difference between the AUC 0-t of tramadol in plasma (414.04 ± 149.25 μg•min/mL) and CSF (221.81 ± 83.02 μg•min/mL) in the i.p. group. In addition, the amounts of metabolites (M1 and M2) in the CSF showed no significant differences following both routes of administration. There were also no significant differences among the K p,uu,CSF(0-360) (0.51 ± 0.12 vs. 0.63 ± 0.04) and K p,uu,CSF(0-∞) (0.61 ± 0.10 vs. 0.62 ± 0.02) for i.v. and i.p. pathways, respectively (p N 0.05). Drug targeting efficiency (DTE) values of tramadol after i.p. injection were more than unity for all scheduled time points. Considering the main analgesic effect of M1, it is hypothesized that both routes of administration may produce the same amount of analgesia.
Pharmacokinetics of intravenous tramadol in dogs
Canadian journal of veterinary research = Revue canadienne de recherche vétérinaire, 2008
The purpose of this study was to determine the pharmacokinetics of tramadol and the active metabolite mono-O-desmethyltramadol (M1) in 6 healthy male mixed breed dogs following intravenous injection of tramadol at 3 different dose levels. Verification of the metabolism to the active metabolite M1, to which most of the analgesic activity of this agent is attributed to, was a primary goal. Quantification of the parent compound and the M1 metabolite was performed using gas chromatography. Pharmacodynamic evaluations were performed at the time of patient sampling and included assessment of sedation, and evaluation for depression of heart and respiratory rates. This study confirmed that while these dogs were able to produce the active M1 metabolite following intravenous administration of tramadol, the M1 concentrations were lower than previously reported in research beagles. Adverse effects were minimal, with mild dose-related sedation in all dogs and nausea in 1 dog. Analgesia was not d...
Assessment of Tramadol Blood Concentration in Cases of Acute Tramadol Overdose
The Egyptian Journal of Forensic Sciences and Applied Toxicology, 2020
Background: Tramadol is a synthetic analgesic drug that has been used for acute and chronic pain. It has a potential risk of addiction and overdoses due to its common illegal abuse. The analgesic effect of tramadol is dose dependent and in medical literature no study evaluates its blood concentrations in overdose and its relation to outcome. Objective: the aim of this study was to evaluate the relation between tramadol blood Level and the different severity grade and outcome in tramadol overdose. Methodology: this study included patients admitted to poisoning control centre Ain Shams University hospitals with tramadol overdose from January 2016 to July 2016. All patients subjected to demographic, clinical, and laboratory evaluation including estimation of tramadol blood level at admission. Results: 91patients included in the study, 67% were due to drug abuse, 39 % of the patients had minor manifestation, 21% had moderate manifestation and 32% had major manifestation. The mortality r...
Pharmacokinetic evaluation of a new oral sustained release dosage form of tramadol
British Journal of Clinical Pharmacology, 2003
To compare the pharmacokinetic profile of a new modified release formulation of tramadol (Tramadol LP 200 mg, SMB Technology, Marche-en-Famenne, Belgium) with that of an immediate release capsule (Topalgic® 50 mg, Grünenthal, Aachen, Germany) after single and multiple dosing and to assess the potential effect of food on its relative bioavailability.
Parent-Metabolite pharmacokinetic models for tramadol-tests of assumptions and predictions
Allometric principles were used to discern cross-species differences in (±)-tramadol disposition and formation of its primary analgesic metabolite, (±)-O-desmethyl-tramadol (M1). Species differences in formation of M1 may help predict the analgesic effectiveness of tramadol. Tramadol was administered intravenously by a zero-order (constant infusion) process or rapid bolus dose and racemic concentrations of tramadol and M1 measured. Data were pooled to define differences between species (human, rat, cat, dog, goat, donkey and horse). A two-compartment linear disposition model with first-order elimination was used to describe tramadol and M1 disposition. Slow metabolizers were detected in 6% of the population and tramadol clearance to M1 was 16.2% that of extensive metabolizers. Tramadol clearance to M1 was slower and tramadol clearance by other pathways was faster in rats, dogs, and horses compared to humans. There are substantial differences between species in the pharmacokinetics of tramadol and its M1 metabolite, which are not explained by differences in body weight. The hypothesis that volumes of distribution are similar across species was shown not to be true. M1 exposure in the goat, donkey and cat was comparable to humans, which indicates it is likely to be an effective analgesic at typically used doses in these species but not in dogs or horses.
The Veterinary Journal, 2009
The study evaluated the pharmacokinetics of tramadol and its major metabolites O-desmethyltramadol (M1), N-desmethyltramadol (M2) and N-O didesmethyltramadol (M5) following a single oral administration of a sustained release (SR) 100 mg tablet to dogs. Plasma tramadol concentration was greater than the limit of quantification (LOQ) in three dogs, M1 was quantified only in one dog while M2 and M5 were quantified in all of the dogs. The median values of C max (maximum plasma concentration), T max (time to maximum plasma concentration) and T 1/2 (half-life) for tramadol were 0.04 (0.17-0.02) lg mL À1 , 3 (4-2) and 1.88 (2.211-1.435) h, respectively. M5 showed median values of C max , T max and T 1/2 of 0.1 (0.19-0.09) lg mL À1 , 2 (3-1) and 4.230 (6.583-1.847) h, respectively. M2 showed median values of C max , T max and T 1/2 of 0.22 (0.330-0.080) lg mL À1 , 4 (7-3) and 4.487 (6.395-1.563) h, respectively. The findings suggest that the SR formulation of tramadol may not have suitable pharmacokinetic characteristics to be administered once-a-day as an effective and safe treatment for pain in the dog.
The kinetics of tramadol at 3 mg/kg was studied in twenty four local dogs (twelve males and twelve females), after a single intravenous and subcutaneous dose administration. Three milliliters of blood from the jugular vein were collected before and at 2, 5, 10, 15, 30 and 45 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 9 h post administration of tramadol from both groups with the exception of 2 min for subcutaneous group. The collected blood samples were analyzed using a high performance liquid chromatography. In male dogs, the maximum plasma concentration (Cmax) was attained (Tmax) much faster (0.17 h) and systemic bioavailability was higher (29.65±11.7%) than in female dogs with 15.68±4.19%. On the other hand, AUC, t 1/2α , t 1/2β Vd (ss) were not significantly different between male and female dogs. These findings suggest the presence of some differences in the kinetics of tramadol between the male and female dogs.
Determination of oral tramadol pharmacokinetics in horses
Research in Veterinary Science, 2010
The determination of the pharmacokinetic parameters of tramadol in plasma and a better characterization of its metabolites after oral administration to horses is necessary to design dosage regimens to achieve target plasma concentrations that are associated with analgesia. The purpose of this study was to determine the pharmacokinetics and elimination pattern in urine of tramadol and its metabolites after oral administration to horses. Tramadol was administered orally to six horses and its half-life, T max and C max in plasma were 10.1, 0.59 h, and 132.7 ng/mL, respectively. The half-life, T max and C max for M1 in plasma were 4.0, 0.59 h, and 28.0 ng/mL, respectively. Tramadol and its metabolites were detectable in urine between 1 and 24 h after the administration. In conclusion, the PK data reported in this study provides information for the design of future studies of tramadol in horses.
Pharmacokinetics of tramadol in children after i.v. or caudal epidural administration
British Journal of Anaesthesia, 2000
We have studied the pharmacokinetics of a single bolus dose of tramadol 2 mg kg-1 injected either i.v. or into the caudal epidural space in 14 healthy children, aged 1-12 yr, undergoing elective limb, urogenital or thoracic surgery. Serum concentrations of tramadol and its metabolite O-demethyl tramadol (M1) were measured in venous blood samples at various intervals up to 20 h by non-stereoselective gas chromatography with nitrogen-selective detection. All pharmacokinetic variables were evaluated using a non-compartmental model. After a single i.v. injection (nϭ9), the mean elimination half-life of tramadol was 6.4 (SD 2.7) h, with a volume of distribution of 3.1 (1.1) litre kg-1 and total plasma clearance of 6.1 (2.5) ml kg-1 min-1. All of these pharmacokinetic variables were similar to those reported previously in adults. After caudal epidural administration (nϭ5), mean elimination half-life was 3.7 (0.9) h, volume of distribution was 2.0 (0.4) litre kg-1 and total clearance was 6.6 (1.9) ml kg-1 min-1. The caudal/i.v. quotient of the AUC was 0.83, which confirms that there is extensive systemic absorption of tramadol after caudal administration. Serum concentrations of M1 showed a time course typical of a metabolite after both modes of administration. Serum concentrations of M1 after caudal administration were lower than those after i.v. injection.