PHARMACOKINETICS OF TRAMADOL AND O-DESMETHYLTRAMADOL IN GIANT TORTOISES (CHELONOIDIS VANDENBURGHI, CHELONOIDIS VICINA).

The objective of this study was to determine the pharmacokinetics of two orally administered doses of tramadol (1 mg/kg and 5 mg/kg) and its metabolite, O-desmethyltramadol (M1) in giant tortoises (Chelonoidis vandenburghi, Chelonoidis vicina). Eleven giant tortoises (C. vandenburghi, C. vicina) received two randomly assigned, oral doses of tramadol (either 1 mg/kg or 5 mg/kg), with a washout period of 3 wk between each dose. The half-life (t½) of orally administered tramadol at 1 mg/kg and 5 mg/kg was 11.9 ± 4.6 h and 13.2 ± 6.1 h, respectively. After oral administration of tramadol at 1 mg/kg and 5 mg/kg, the maximum concentration (Cmax) was 125 ± 69 ng/ml and 518 ± 411 ng/ml, respectively. There were not enough data points to determine pharmacokinetic (PK) parameters for the M1 metabolite from either dose. Tramadol administered orally to giant tortoises at both doses provided measurable plasma concentrations of tramadol for approximately 48 h with occasional transient sedation. Oral tramadol at 5 mg/kg, on average, achieves concentrations of >100 ng/ml, the reported human therapeutic threshold, for 24 h. Based on the low levels of M1 seen in this study, M1 may not be a major metabolite in this taxon.

Intoxication by 3-MeO-PCP and O-desmethyltramadol: an unusual NPS mix.

Over the past few years, the new psychoactive substances' phenomenon has been continuously studied. Its dynamic context is characterized by a broad diversity of substances, including several groups, such as synthetic cathinones, synthetic opiates, and synthetic cannabinoids. However, and due both to this diversity and to the low number of detected cases, information on intoxication reports is always important, in order to understand their biological mechanisms. In this case, a male individual was found unresponsive, with some different powders and paraphernalia near him. After toxicological analysis to the powders, paraphernalia, and whole blood samples, five different compounds were identified. From these, two of them (3-MeO-PCP and o-desmethyltramadol) were identified and quantitated in the whole blood sample. The obtained results suggested that death was due to the presence and action of these two substances, in what may be considered an unusual mix of NPS. This case highlights the value of evaluating all the traces found in the scene investigation and the need of sending all the paraphernalia found for toxicological examination, together with all the possible information obtained on the scene, namely by relatives or witnesses. On the other hand, this case shows the significance of broad-spectrum analytical methods, in order to detect and identify, as specifically as possible, eventual substances present and used by victims.

Population Pharmacokinetic Model for Tramadol and O-desmethyltramadol in Older Patients.

BACKGROUND AND OBJECTIVES: Tramadol is commonly prescribed to manage chronic pain in older patients. However, there is a gap in the literature describing the pharmacokinetic parameters for tramadol and its active metabolite (O-desmethyltramadol [ODT]) in this population. The objective of this study was to develop and evaluate a population pharmacokinetic model for tramadol and ODT in older patients. METHODS: Twenty-one patients who received an extended-release oral tramadol dose (25-100 mg) were recruited. Tramadol and ODT concentrations were determined using a validated liquid chromatography/tandem mass spectrometry method. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. The performance of the model was assessed by visual predictive check. RESULTS: A two-compartment, first-order absorption model with linear elimination best described the tramadol concentration data. The absorption rate constant was 2.96/h (between-subject variability [BSV] 37.8%), apparent volume of distribution for the central compartment (V1/F) was 0.373 l (73.8%), apparent volume of distribution for the peripheral compartment (V2/F) was 0.379 l (97.4%), inter-compartmental clearance (Q) was 0.0426 l/h (2.19%) and apparent clearance (CL/F) was 0.00604 l/h (6.61%). The apparent rate of metabolism of tramadol to ODT (kt) was 0.0492 l/h (78.5%) and apparent clearance for ODT (CLm) was 0.143 l/h (21.6%). Identification of Seniors at Risk score (ISAR) and creatinine clearance (CrCL) were the only covariates included in the final model, where a higher value for the ISAR increased the maximum concentration (Cmax) of tramadol and reduced the BSV in Q from 4.71 to 2.19%. A higher value of CrCL reduced tramadol Cmax and half-life (T1/2) and reduced the BSV in V2/F (from 148 to 97.4%) and in CL/F (from 78.9 to 6.61%). CONCLUSION: Exposure to tramadol increased with increased frailty and reduced CrCL. Prescribers should consider patients frailty status and CrCL to minimise the risk of tramadol toxicity in such cohort of patients.

Physiologically Based Pharmacokinetic Modeling to Assess the Impact of CYP2D6-Mediated Drug-Drug Interactions on Tramadol and O-Desmethyltramadol Exposures via Allosteric and Competitive Inhibition.

Tramadol is an opioid medication used to treat moderately severe pain. Cytochrome P450 (CYP) 2D6 inhibition could be important for tramadol, as it decreases the formation of its pharmacologically active metabolite, O-desmethyltramadol, potentially resulting in increased opioid use and misuse. The objective of this study was to evaluate the impact of allosteric and competitive CYP2D6 inhibition on tramadol and O-desmethyltramadol pharmacokinetics using quinidine and metoprolol as prototypical perpetrator drugs. A physiologically based pharmacokinetic model for tramadol and O-desmethyltramadol was developed and verified in PK-Sim version 8 and linked to respective models of quinidine and metoprolol to evaluate the impact of allosteric and competitive CYP2D6 inhibition on tramadol and O-desmethyltramadol exposure. Our results show that there is a differentiated impact of CYP2D6 inhibitors on tramadol and O-desmethyltramadol based on their mechanisms of inhibition. Following allosteric inhibition by a single dose of quinidine, the exposure of both tramadol (51% increase) and O-desmethyltramadol (52% decrease) was predicted to be significantly altered after concomitant administration of a single dose of tramadol. Following multiple-dose administration of tramadol and a single-dose or multiple-dose administration of quinidine, the inhibitory effect of quinidine was predicted to be long (≈42 hours) and to alter exposure of tramadol and O-desmethyltramadol by up to 60%, suggesting that coadministration of quinidine and tramadol should be avoided clinically. In comparison, there is no predicted significant impact of metoprolol on tramadol and O-desmethyltramadol exposure. In fact, tramadol is predicted to act as a CYP2D6 perpetrator and increase metoprolol exposure, which may necessitate the need for dose separation.

HPLC-UV assay of tramadol and O-desmethyltramadol in human plasma containing other drugs potentially co-administered to participants in a paediatric population pharmacokinetic study.

Multimodal analgesia is employed in paediatric pain management to maximise analgesia and minimise side effects. Tramadol is dosed at 1-1.5 mg/kg to treat severe pain in children but the assay for tramadol in plasma samples for pharmacokinetic and toxicology studies does not often consider concurrently administered medications. In this study we developed and validated an HPLC-UV method to quantify tramadol and its main metabolite (O-desmethyltramadol) in human plasma in the presence of seven potentially interfering drugs. Sample preparation method was developed by combining liquid-liquid extraction and protein precipitation. Chromatographic separation was achieved on a BDS-Hypersil-C18 column (5 µm, 250 × 4.6 mm) using a double gradient method. The limit of quantification was 6.7 ng/ml for both tramadol and ODT. The precision and accuracy were in compliance with ICH guidelines. This method was successfully employed to analyse the blood samples of 137 paediatric participants in a tramadol pharmacokinetic trial.

Hepatotoxic effect of tramadol and O-desmethyltramadol in HepG2 cells and potential role of PI3K/AKT/mTOR.

1. The aim of this study was to compare the in vitro cytotoxic effect of tramadol and M1 metabolite in HepG2 cell line, the underlying mechanism, and PI3K/AKT/mTOR as potential target.2. Concentrations representing therapeutic level for tramadol (2 µM) and M1 metabolite (0.5 µM) were used. In addition, other increasing concentrations representing higher toxic levels were used (6, 10 µM for tramadol and 1.5, 2.5 µM for M1 metabolites). Cytotoxicity was assessed at 24, 48 and 72 h.3. Both tramadol and M1 metabolites were able to produce cytotoxicity in a dose and time dependent manner. Insignificant difference was detected between cells exposed to tramadol and M1 metabolite at therapeutic concentrations. Tramadol-induced apoptotic and autophagic cell death while M1 metabolite-induced apoptosis only. For PI3K/AKT/mTOR pathway, the therapeutic concentration of tramadol was only able to increase phosphorylation of AKT while higher toxic concentrations were able to increase phosphorylation of whole pathway; Meanwhile, M1 metabolite was able to increase the phosphorylation of the whole pathway significantly in therapeutic and toxic concentrations.4. In conclusion, both tramadol and M1 are equally cytotoxic. Apoptosis and autophagy both mediate hepatic cell death. PI3K/AKT pathway is involved in apoptosis induction while autophagy is regulated through mTOR independent pathway.

Simultaneous LC-MS/MS quantification of oxycodone, tramadol and fentanyl and their metabolites (noroxycodone, oxymorphone, O- desmethyltramadol, N- desmethyltramadol, and norfentanyl) in human plasma and whole blood collected via venepuncture and volumetric absorptive micro sampling.

INTRODUCTION: A range of opioids are commonly prescribed to manage chronic pain, but individual patient responses vary greatly, especially in older populations. One source of that variability are differences in absorption, metabolism and excretion, i.e. pharmacokinetics. Blood, plasma and serum concentrations of opioids allow that variability to be quantified and may be used to optimise opioid dosing. As an aid to that process, there is an unmet need to rapidly quantify several opioids and their metabolites in a single analytical method. AIMS: To develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of tramadol, oxycodone, fentanyl and their major metabolites in various human matrices. METHODS: Sample preparation involved adding three deuterated internal standards followed by protein precipitation with 100 % acetonitrile, evaporation and reconstitution. Separation of analytes via LC was achieved on a reversed phase column via binary gradient elution using 0.005 % formic acid in water and 100 % acetonitrile as mobile phases. Analytes were detected via MS/MS with multiple reaction monitoring (MRM). RESULTS: The method was accurate with the inter-day and intra-day accuracy of quality control samples (QCs) below 15 %. It was also precise with inter-day and intra-day coefficient of variation below 15 %. The lower limit of quantification (LLOQ) was 0.2 ng/mL for all analytes except tramadol and its metabolites, where the LLOQ was 10 ng/mL. Recovery was greater than 88 % for all analytes, except for O-desmethyltramadol (81 %). Analytes were stable over four freeze-thaw cycles, for 24 h on the bench top and for 24 h post-preparation. The inter- and intra-day variability of concentrations determined in blood and plasma were within 84-124%, whereas the inter- and intra-day variability for blood samples prepared using volumetric absorptive micro-sampling (VAMS) compared to those prepared from whole blood ranged between 83-122%. CONCLUSION: A LC-MS/MS method is described that is able to accurately and precisely quantify a number of commonly prescribed opioids and their major metabolites in plasma and whole blood, including whole blood collected using VAMS.

Pharmacokinetic profile of injectable tramadol in the koala (Phascolarctos cinereus) and prediction of its analgesic efficacy.

Tramadol is used as an analgesic in humans and some animal species. When tramadol is administered to most species it undergoes metabolism to its main metabolites M1 or O-desmethyltramadol, and M2 or N-desmethyltramadol, and many other metabolites. This study describes the pharmacokinetic profile of tramadol when a single subcutaneous bolus of 2 mg/kg was initially administered to two koalas. Based on the results of these two koalas, subsequently 4 mg/kg as a single subcutaneous injection, was administered to an additional four koalas. M1 is recognised as an active metabolite and has greater analgesic activity than tramadol, while M2 is considered inactive. A liquid chromatography assay to quantify tramadol, M1 and M2 in koala plasma was developed and validated. Liquid chromatography-mass spectrometry confirmed that M1 had been identified. Additionally, the metabolite didesmethyltramadol was identified in chromatograms of two of the male koalas. When 4 mg/kg tramadol was administered, the median half-life of tramadol and M1 were 2.89 h and 24.69 h, respectively. The M1 plasma concentration remained well above the minimally effective M1 plasma concentration in humans (approximately 36 ng/mL) over 12 hours. The M1 plasma concentration, when tramadol was administered at 2 mg/kg, did not exceed 36 ng/mL at any time-point. When tramadol was administered at 2 mg/kg and 4 mg/kg the area under the curve M1: tramadol ratios were 0.33 and 0.50, respectively. Tramadol and M1 binding to plasma protein were determined using thawed, frozen koala plasma and the mean binding was 20% and 75%, respectively. It is concluded that when tramadol is administered at 4 mg/kg as a subcutaneous injection to the koala, it is predicted to have some analgesic activity.

Evaluation of tramadol human pharmacokinetics and safety after co-administration of magnesium ions in randomized, single- and multiple-dose studies.

BACKGROUND: Magnesium ions (Mg2+) increase and prolong opioid analgesia in chronic and acute pain. The nature of this synergistic analgesic interaction has not yet been explained. Our aim was to investigate whether Mg2+ alter tramadol pharmacokinetics. Our secondary goal was to assess the safety of the combination. METHODS: Tramadol was administered to healthy Caucasian subjects with and without Mg2+ as (1) single 100-mg and (2) multiple 50-mg oral doses. Mg2+ was administered orally at doses of 150 mg and 75 mg per tramadol dosing in a single- and multiple-dose study, respectively. Both studies were randomized, open label, laboratory-blinded, two-period, two-treatment, crossover trials. The plasma concentrations of tramadol and its active metabolite, O-desmethyltramadol, were measured. RESULTS: A total of 25 and 26 subjects completed the single- and multiple-dose study, respectively. Both primary and secondary pharmacokinetic parameters were similar. The 90% confidence intervals for Cmax and AUC0-t geometric mean ratios for tramadol were 91.95-102.40% and 93.22-102.76%. The 90% confidence intervals for Cmax,ss and AUC0-τ geometric mean ratios for tramadol were 93.85-103.31% and 99.04-105.27%. The 90% confidence intervals for primary pharmacokinetic parameters were within the acceptance range. ANOVA did not show any statistically significant contribution of the formulation factor (p > 0.05) in either study. Adverse events and clinical safety were similar in the presence and absence of Mg2+. CONCLUSIONS: The absence of Mg2+ interaction with tramadol pharmacokinetics and safety suggests that this combination may be used in the clinical practice for the pharmacotherapy of pain.

Impact of CYP2D6 activity and cachexia progression on enantiomeric alteration of plasma tramadol and its demethylated metabolites and their relationships with central nervous system symptoms in head and neck cancer patients.

This study aimed to evaluate the influence of CYP2D6 activity and cachexia progression on the enantiomeric alteration of plasma tramadol and its demethylated metabolites in head and neck cancer patients. Fifty-three head and neck cancer patients receiving oral tramadol were enrolled. The plasma concentrations of tramadol, O-desmethyltramadol (ODT) and N-desmethyltramadol (NDT) enantiomers were determined. The CYP2D6 activity score (AS) and degree of cachexia progression were assessed according to genotype and the Glasgow Prognostic Score (GPS), respectively. The enantiomeric ratio of NDT was (+)-form dominant in all patients. CYP2D6 AS had negative correlations with the plasma concentrations of (+)-NDT and (-)-NDT. The plasma concentrations of (+)-tramadol and (+)-ODT were higher in patients with GPS 1 or 2 than in those with GPS 0. Lower metabolic ratios to NDT enantiomers were observed in patients with GPS 1 or 2. In patients with GPS 1 or 2, the plasma (-)-tramadol was associated with the incidence of central nervous system symptoms. In conclusion, CYP2D6 AS partially explained the contribution of CYP2D6 activity to plasma tramadol and its demethylated metabolite enantiomers. Additionally, cachexia progression elevated the plasma (+)-tramadol and (+)-ODT levels through the reduction of N-demethylation of (+)-tramadol.

Temporal patterns of tramadol in hair after a single dose.

This controlled study aimed to measure concentrations of tramadol (TRA) and its two main metabolites, N-desmethyltramadol (NDMT) and O-desmethyltramadol (ODMT), in hair following a single dose ingestion and to investigate the distribution patterns in hair by segmental analysis of hair samples taken at several sampling time points after ingestion. An oral dose (50 or 100mg) of TRA was administered to 17 healthy volunteers. Hair samples were collected prior to drug administration and 14, 30, 60 and 120 days after ingestion. Each sample was segmented in 5mm segments and washed. The analytes were extracted from pulverized hair by incubation in extraction media for 18h at 37°C. A validated UHPLC-MS/MS method was used to quantify the analytes at a LLOQ of 0.001ng/mg. Hair segments corresponding to the time of ingestion were positive for TRA and the metabolites of each sampling time point, although neighboring segments also showed positive results. The highest concentrations for both dosage groups were observed in the proximal segment of hair collected 14 days after ingestion for all subjects: 0.061-0.95ng TRA/mg, 0.012-0.86ng NDMT/mg and 0.009-0.17ng ODMT/mg (n=16). Generally, the TRA concentration was higher than the metabolites concentrations but depended on the CYP2D6 phenotype. The metabolite to TRA ratios were stable within a subject over the sampling time points, however it varied greatly between subjects. No significant differences in hair concentrations were found between the two dosage groups at each sampling time. Several confounding factors were identified such as hair pigmentation and internal sweat. We showed that analysis of 5mm segments improved the determination of the exposure time after a single ingestion of TRA. In addition, in the later sampling time points the analytes were spread more between segments and the total drug amount of each later sampling time point declined up to a 100% (median: 75%) due to wash out. The presented results are important additions to the sparse literature reporting single dose of psychoactive drugs in hair.

Automated high-throughput analysis of tramadol and O-desmethyltramadol in dried blood spots.

The World Anti-Doping Agency (WADA) and the International Testing Agency (ITA) recently announced the development and implementation of dried blood spot (DBS) testing for routine analysis in time for the 2022 Winter Olympic and Paralympic Games in Beijing. Following the introduction of a ban on the use of tramadol in competition in March 2019, the Union Cycliste International (UCI) started a pilot study for the manual analysis of tramadol in DBS for antidoping purposes. In this context, we present a fully automated LC-MS/MS-based method with automated sample preparation using a CAMAG DBS-MS 500 for the analysis of tramadol and its metabolite O-desmethyltramadol in DBS. The presented approach reduces manual handling in the laboratory to an absolute minimum, only requiring the preparation of calibration and quality control DBS cards. The method was developed, optimized, and validated before performing cross-validation with a liquid blood-based analysis method using authentic samples from forensic cases. During the validation process, the method showed an extraction efficiency of 62%, linearity r2 > 0.99, accuracy and precision (within ± 15% and ± 20% at the LLOQ) for the determination of tramadol and O-desmethyltramadol. Method comparison in liquid blood with 26 samples showed good agreement (90 ± 19% for tramadol and 94 ± 14% for O-desmethyltramadol). In conclusion, automated analysis of tramadol and O-desmethyltramadol in DBS provides a fast and accurate solution for antidoping screening. It is suited for high-throughput analysis, having a run time of about 4 min per sample. Furthermore, with the automated approach, manual sample extraction becomes obsolete.

Intrinsic clearance rate of O-desmethyltramadol (M1) by glucuronide conjugation and phase I metabolism by feline, canine and common brush-tailed possum microsomes.

Quantitative aspects of in vitro phase II glucuronidative metabolism of O-desmethyltramadol (O-DSMT or M1), the active metabolite of the analgesic drug tramadol, by feline, canine and common brush-tailed possum hepatic microsomes are described.Whilst previous studies have focused on the phase I conversion of tramadol to M1, this is the first report in which the phase II glucuronidative metabolic pathway of M1 has been isolated by an in vitro comparative species study.Using the substrate depletion method, microsomal phase II glucuronidative in vitro intrinsic clearance (Clint) of M1 was determined.The in vitro Clint (mean ± SD) by pooled common brush-tailed possum microsomes was 9.9 ± 1.7 µL/min/mg microsomal protein whereas the in vitro Clint by pooled canine microsomes was 1.9 ± 0.07 µL/min/mg microsomal protein. The rate of M1 depletion by feline microsomes, as measured solely by high pressure liquid chromatography, was too slow to determine. Liquid chromatography-mass spectrometry identified O-DSMT glucuronide in samples generated from all three species' microsomes, although the amount detected under the feline condition was minimal.This study indicates that M1 likely undergoes in vitro phase II glucuronidation by canine and common brush-tailed possum microsomes and, to a minor extent, by feline microsomes. The rate of depletion of M1 by phase I metabolism was also undertaken.When incubated with phase I co-factors and common brush-tailed possum microsomes or canine microsomes, M1 had an in vitro Clint of 47.6 and 22.8 µL/min/mg microsomal protein, respectively. However, due to a lack of CYP2B-like activity in the feline liver, unsurprisingly, M1 did not deplete when incubated with feline microsomes. Consequently, major M1 elimination pathways, using feline microsomes, were not determined."

A Reversed-Phase Mode LC-MS/MS Method Using a Polysaccharide Chiral Selector for Simultaneous Quantitation of Each Enantiomer of Tramadol and its Metabolites in Human Plasma and Evaluation of CYP-Mediated Stereoselective Demethylation.

BACKGROUND: The enantiomeric pharmacokinetics and metabolism of tramadol and its metabolites have not fully been understood. This study aimed to develop a reversed-phase mode liquid chromatography coupled to a tandem mass spectrometry method for the enantiomeric quantitation of tramadol and its metabolites in human plasma and to evaluate the stereoselective demethylation. METHODS: Racemic tramadol and its metabolites in plasma specimens were separated using a chiral selector coated with cellulose tris(3,5-dimethylphenylcarbamate) on silica gel under a reversed-phase mode. The mass spectrometer ran in the positive ion multiple-reaction monitoring mode. This method was performed to quantify plasma samples from 20 cancer patients treated with oral tramadol. The stereoselective demethylation was evaluated using recombinant cytochrome P450 (CYP) enzymes. RESULTS: The calibration curves of (+)- and (-)-tramadol, (+)- and (-)-O-desmethyltramadol (ODT), and (+)- and (-)-N-desmethyltramadol (NDT) were linear over the plasma concentration ranges of 6.25-800, 1.25-160, and 3.13-400 ng/mL for the respective enantiomers. In the present method, the intra- and inter-day accuracies and imprecisions were 94.2%-108.3% and 0.5%-6.0% for all analytes. The plasma concentrations of (+)-tramadol and NDT were higher than those of (-)-enantiomers. In contrast, no differences were observed between the plasma concentrations of (+)- and (-)-ODT. In the demethylation assay, the O-demethylations of tramadol and NDT by CYP2D6 were (-)-form-selective. CONCLUSIONS: The present method can be useful in the enantiomeric evaluation of tramadol and its metabolites in human plasma. Although CYP2D6 contributed to the stereoselective demethylation of tramadol, remarkable differences between (+)- and (-)-ODT were not observed in the plasma of the cancer patients.

Population pharmacokinetic analysis of tramadol and O-desmethyltramadol with genetic polymorphism of CYP2D6.

Aim: Tramadol is widely used to treat acute, chronic, and neuropathic pain. Its primary active metabolite, O-desmethyltramadol (M1), is mainly responsible for its µ-opioid receptor-related analgesic effect. Tramadol is metabolized to M1 mainly by the cytochrome P450 (CYP) 2D6 enzyme, and to other metabolites by CYP3A4 and CYP2B6. The aim of this study was to develop a population pharmacokinetic (PK) model of tramadol and its metabolite using healthy Korean subjects. Methods: Data on plasma concentrations of tramadol and M1 were obtained from 23 healthy Korean male subjects after a twice-daily oral dose of 100 mg of tramadol, every 12 hrs, for a total of 5 times. Blood samples were collected at 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hrs after last administration. Plasma tramadol concentrations were then analyzed using LC/MS. Population PK analysis of tramadol and its metabolite was performed using a nonlinear mixed-effects modeling (NONMEM). Results: A one-compartment model with combined first-order and zero-order absorption was well fitted to the concentration-time curve of tramadol. M1 was well described by the one-compartment model as an extension of the parent drug (tramadol) model. Genetic polymorphisms of CYP2D6 correlated with the clearance of tramadol, and clearance from the central compartment to the metabolite compartment. Conclusion: The parent-metabolite model successfully characterized the PK of tramadol and its metabolite M1 in healthy Korean male subjects. These results could be applied to evaluate plasma tramadol concentrations after various dosing regimens.

Population Pharmacokinetic/Pharmacodynamic Modeling of O-Desmethyltramadol in Young and Elderly Healthy Volunteers.

BACKGROUND: Age-related changes in the concentration-effect relationship of (+)-O-desmethyl-tramadol [(+)-ODM], tramadol's active metabolite, are not documented in the elderly. OBJECTIVE: The objective of this study was to characterize, in elderly and young subjects, the (+)-ODM pharmacokinetic and pharmacodynamic relationship to examine the effect of age after single-dose administration of tramadol 200 mg extended-release tablets. METHODS: A population analysis of a double-blind, randomized, placebo-controlled, two-period cross-over study including 13 elderly (aged ≥75 years) subjects with mild renal insufficiency and 16 young (aged 18-40 years) subjects was conducted. For 48 h post-dose, blood samples were collected and pain tolerance thresholds measured using an electrically stimulated pain model. A pharmacokinetic/pharmacodynamic model incorporating a one-compartment pharmacokinetic model for (+)-ODM parameterized with first-order formation rate, clearance (CL/fm), volume of distribution (V/fm) and a sigmoid maximum effect (Emax) model incorporating baseline (E0) and placebo effect was used. RESULTS: Maximum plasma concentrations of (+)-ODM occurred later and plasma concentrations declined more slowly in the elderly than in young subjects. In the elderly, V/fm was 76% larger and CL/fm 16% slower. Baseline (E0) and sensitivity (C50) for pain tolerance were similar between young and elderly subjects. However, the Emax parameter was 2.5 times higher in the elderly and maximum possible treatment-related effect was 169 (135-221) in the young and 194 (149-252) in the elderly; that is, 15% higher in the elderly. CONCLUSIONS: This exploratory analysis suggests that age-related differences exist in the distribution and elimination of (+)-ODM, including a 76% larger distribution outside the central compartment and 16% slower clearance of (+)-ODM. These pharmacokinetic changes are associated with a 15% higher maximum possible treatment-related effect and carry the potential for greater efficacy but also the potential for increased side effects at the same dose in elderly subjects. Clinicaltrials.gov identifier: NCT02329561.

Desmetramadol Has the Safety and Analgesic Profile of Tramadol Without Its Metabolic Liabilities: Consecutive Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Trials.

Desmetramadol is an investigational analgesic consisting of (+) and (-) enantiomers of the tramadol metabolite O-desmethyltramadol (M1). Tramadol is racemic and exerts analgesia by monoaminergic effects of (-)-tramadol and (-)-M1, and by the opioid (+)-M1. Tramadol labeling indicates cytochrome P450 (CYP) isozyme 2D6 ultrarapid metabolizer can produce dangerous (+)-M1 levels, and CYP2D6 poor metabolizers insufficient (+)-M1 for analgesia. We hypothesized that desmetramadol could provide the safety and analgesia of tramadol without its metabolic liabilities. We conducted consecutive double-blind, randomized, placebo-controlled, 3 segment cross-over trials A and B to investigate the steady-state pharmacokinetics and analgesia of 20 mg desmetramadol and 50 mg tramadol in 103 healthy participants without (n = 43) and with (n = 60) cotreatment with the CYP inhibitor paroxetine. In the absence of CYP inhibition (trial A), 20 mg desmetramadol and 50 mg tramadol dosed every 6 hours gave equivalent steady-state (+)-M1, similar adverse events, and analgesia significantly greater than placebo, but equal to each other. In trial B, CYP inhibition significantly depressed tramadol steady-state (+)-M1, reduced its adverse events, and led to insignificant analgesia comparable with placebo. In contrast, CYP inhibition in trial B had no deleterious effect on desmetramadol (+)-M1 or (-)-M1, which gave significant analgesia as in trial A and superior to tramadol (P = .003). Desmetramadol has the safety and efficacy of tramadol without its metabolic liabilities. CLINICALTRIALS.GOV REGISTRATIONS: NCT02205554, NCT03312777 PERSPECTIVE: To our knowledge, this is the first study of desmetramadol in humans and the first to show it provides the same safety and analgesia as tramadol, but without tramadol's metabolic liabilities and related drug-drug interactions. Desmetramadol could potentially offer expanded safety and usefulness to clinicians seeking an alternative to schedule II opioids.

Development and validation of an HPLC-UV method for simultaneous determination of sildenafil and tramadol in biological fluids: Application to drug-drug interaction study.

The introduction of sildenafil (SDF) to treat erectile dysfunction has solved a widespread condition with negative on the quality of life. Recently, the co-administration of tramadol (TMD) with SDF to manage premature ejaculation has illegally increased and thus drug-drug interaction studies of these drugs became of great importance. Although certain biological functions have been altered upon co-administration of the two drugs, methods for their determination in vivo to understand their interactions have yet to be published. Herein, therefore, an HPLC method with photometric detection was developed for the determination of a binary mixture of TMD and SDF in rabbit plasma after oral administration. In this study, a reversed-phase chromatography was performed at room temperature on a C18 column with a mobile phase composed of 10 mM Na2HPO4 solution (pH 7.5): acetonitrile (45:55, v/v) at a flow rate of 0.8 mL min-1 using caffeine (CAF) as an internal standard. The detector was set at 220 nm. The total analysis time was 6 min. Calibration graphs were linear in the concentration ranges of 0.1-10 and 0.05-10 µg mL-1 with a detection limit of 0.05 and 0.02 µg mL-1 for TMD and SDF, respectively. The method was validated in terms of accuracy, precision, limit of detection and quantitation, recovery, and stability as per US FDA bioanalytical guidelines. In addition, the metabolites N-desmethylsildenafil (UK-103,320) and O-desmethyltramadol were quantified in rabbit plasma after 2 h of oral administration using LC-MS/MS. The simultaneous administration of TMD with SDF has affected peak plasma concentration (Cmax), Tmax, area under the concentration-time curve (AUC), and the elimination rate constant (Kel) of SDF. The present study is the first to give valuable insights into the drug-drug interaction and the pharmacokinetic implications associated with the co-administration of SDF and TMD.

Influence of Obesity and Type 2 Diabetes Mellitus on the Pharmacokinetics of Tramadol After Single Oral Dose Administration.

BACKGROUND AND OBJECTIVES: The number of overweight, obese and diabetic patients is constantly increasing. Metabolic disorders may affect the pharmacokinetics of drugs, e.g., by altering the activity of cytochrome P450 (CYP) isoenzymes. Tramadol is a commonly used analgesic metabolised mainly via CYP2D6 to its active metabolite, O-desmethyltramadol. The aim of the study was to assess the influence of overweight, obesity and type 2 diabetes mellitus on tramadol and O-desmethyltramadol pharmacokinetics. METHODS: All patients received a single oral dose (100 mg) of tramadol. The plasma concentrations of tramadol and O-desmethyltramadol were measured with the validated high-performance liquid chromatography method with fluorescence detection. The pharmacokinetic parameters of tramadol and O-desmethyltramadol were calculated by non-compartmental methods. RESULTS: After nephrectomy, the patients were divided into four groups-a control group (n = 12, mean [SD] age 61 [14] years, body mass index (BMI) 22 [2] kg/m2, CLcr (creatinine clearance) 74 [30] mL/min); an overweight group (n = 15, mean [SD] age 63 [11] years, BMI 27 [1] kg/m2, CLcr 81 [35] mL/min); an obese group (n = 12, mean [SD] age 57 [8] years, BMI 33 [4] kg/m2, CLcr 113 [51] mL/min); and an obese and diabetic group (n = 9, mean [SD] age 64 [10] years, BMI 33 [4] kg/m2, CLcr 87 [35] mL/min). Apart from the time to first occurrence of maximal concentration (tmax), there were no significant differences in the pharmacokinetic parameters of tramadol and O-desmethyltramadol among the groups. Moreover, there were no significant differences in the O-desmethyltramadol/tramadol ratios among the four groups of patients after nephrectomy. CONCLUSIONS: No significant differences were found in the pharmacokinetics of tramadol and O-desmethyltramadol, indicating that the opioid can be administered to overweight, obese and diabetic patients without dosage adjustment.

Identification of opioids in surface and wastewaters by LC/QTOF-MS using retrospective data analysis.

Opioids, both as prescription drugs and abuse substances, have been a hot topic and a focus of discussion in the media for the last few years. Although the literature published shows the occurrence of opioids and some of their metabolites in the aquatic environment, there are scarce data in the application of high resolution mass spectrometry (HRMS) for the analysis of these compounds in the environment. The use of HRMS allows increasing the number of opioids that can be studied as well as the detection of unknown opioids, their metabolites and potential transformation products. In this work, a retrospective analysis for the identification of opioids and their metabolites using a curated database was applied to surface water and wastewater samples taken in the state of Minnesota (U.S.) in 2009, which were previously analyzed by liquid chromatography/time-of-flight mass spectrometry (LC/TOF-MS) for antidepressants. The database comprised >200 opioids including natural opiates (e.g. morphine and codeine), their semi-synthetic derivatives (e.g. heroin, hydromorphone, hydrocodone, oxycodone, oxymorphone, meperidine and buprenorphine), fully synthetic opioids (e.g. fentanyl, methadone, tramadol, dextromethorphan and propoxyphene), as well as some of their metabolites (e.g. 6-monoacetylcodeine, dextrorphan, EDDP, normorphine and O-desmethyltramadol). Moreover, additional MS-MS experiments were performed to confirm their identification, as well as to recognize fragmentation patterns and diagnostic ions for several opioids. These data provide a better understanding of the historical occurrence of opioids and their metabolites in surface waters impacted by wastewater sources. The concentrations of individual opioids in surface water and wastewater effluent varied from 8.8 (EDDP) to 1640 (tramadol) ngL-1 and from 12 (dihydrocodeine) to 1288 (tramadol) ngL-1, respectively. The opioids with higher overall frequency detections were tramadol, dextromethorphan and its metabolite, dextrorphan.