O-Desmethyltramadol

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France Varin - One of the best experts on this subject based on the ideXlab platform.

  • Population Pharmacokinetic/Pharmacodynamic Modeling of O-Desmethyltramadol in Young and Elderly Healthy Volunteers
    Drugs & Aging, 2019
    Co-Authors: Sybil Skinner Robertson, Mohamad-samer Mouksassi, France Varin
    Abstract:

    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/ f _m), volume of distribution ( V / f _m) and a sigmoid maximum effect ( E _max) model incorporating baseline ( E _0) 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 / f _m was 76% larger and CL/ f _m 16% slower. Baseline ( E _0) and sensitivity ( C _50) for pain tolerance were similar between young and elderly subjects. However, the E _max 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.

Sooyeun Lee - One of the best experts on this subject based on the ideXlab platform.

  • Development of a linear dual column HPLC–MS/MS method and clinical genetic evaluation for tramadol and its phase I and II metabolites in oral fluid
    Archives of Pharmacal Research, 2017
    Co-Authors: Hyerim Yu, Jung-woo Bae, Seongkuk Hong, Chul Ho Jeong, Sooyeun Lee
    Abstract:

    Tramadol is a centrally acting synthetic opioid analgesic and has received special attention due to its abuse potential and unexpected responses induced by CYP2D6 polymorphism. Oral fluid is an advantageous biofluid for drug analysis due to non-invasive sampling and high correlation of drug concentrations with plasma. However, few studies have been performed on distribution of tramadol and its metabolites in oral fluid. In the present study, a linear dual column HPLC–MS/MS method was developed and fully validated for the simultaneous determination of tramadol and its phase I [O-Desmethyltramadol (ODMT), N-desmethyltramadol (NDMT) and N,O-didesmethyltramadol (NODMT)] and II metabolites in oral fluid. Furthermore, the distribution of tramadol and its metabolites, in relation to CYP2D6 genetic variations, in oral fluid was investigated following a clinical study including 23 subjects with CYP2D6*wt/*wt, CYP2D6*10/*10 or CYP2D6*5/*5. The validation results of selectivity, matrix effect, linearity, precision and accuracy were satisfactory. Pharmacokinetic parameters, such as Css,max and AUC0–τ of tramadol, NDMT and NODMT, in the CYP2D6*10/*10 group were significantly higher than those in the CYP2D6*wt/*wt group. Moreover, the ratios of ODMT/tramadol, NDMT/tramadol and NODMT/NDMT correlated well with the CYP2D6 genotypes. We demonstrated that oral fluid is a promising biofluid for pharmacokinetic evaluation in relation to genetic variations.

Vera Lucia Lanchote - One of the best experts on this subject based on the ideXlab platform.

  • Enantioselective analysis of unbound tramadol, O-Desmethyltramadol and N-desmethyltramadol in plasma by ultrafiltration and LC–MS/MS: Application to clinical pharmacokinetics
    Journal of Chromatography B, 2011
    Co-Authors: Natália Valadares De Moraes, Gabriela Rocha Lauretti, Marcio Nogueira Napolitano, Naiane Ribeiro Santos, Ana Leonor Pardo Campos Godoy, Vera Lucia Lanchote
    Abstract:

    Abstract This study describes the enantioselective analysis of unbound and total concentrations of tramadol and its main metabolites O-Desmethyltramadol (M1) and N-desmethyltramadol (M2) in human plasma. Sample preparation was preceded by an ultrafiltration step to separate the unbound drug. Both the ultrafiltrate and plasma samples were submitted to liquid/liquid extraction with methyl t-butyl ether. Separation was performed on a Chiralpak® AD column and tandem mass spectrometry consisting of an electrospray ionization source, positive ion mode and multiple reaction monitoring was used as the detection system. Linearity was observed in the following ranges: 0.2–600 and 0.5–250 ng/mL for analysis of total and unbound concentrations of the tramadol enantiomers, respectively, and 0.1–300 and 0.25–125 ng/mL for total and unbound concentrations of the M1 and M2 enantiomers, respectively. The lower limits of quantitation were 0.2 and 0.5 ng/mL for analysis of total and unbound concentration of each tramadol enantiomer, respectively, and 0.1 and 0.25 ng/mL for total and unbound concentrations of M1 and M2 enantiomers, respectively. Intra- and interassay reproducibility and inaccuracy did not exceed 15%. Clinical application of the method to patients with neuropathic pain showed plasma accumulation of (+)-tramadol and (+)-M2 after a single oral dose of racemic tramadol. Fractions unbound of tramadol, M1 or M2 were not enantioselective in the patients investigated.

  • Simultaneous analysis of tramadol, O-Desmethyltramadol, and N-desmethyltramadol enantiomers in rat plasma by high-performance liquid chromatography-tandem mass spectrometry: application to pharmacokinetics.
    Chirality, 2010
    Co-Authors: Ana Leonor Pardo Campos Godoy, Natália Valadares De Moraes, Edson Zangiacomi Martinez, Teresa Maria De Jesus Ponte Carvalho, Maria Paula Marques, Vera Lucia Lanchote
    Abstract:

    Tramadol (T) is available as a racemic mixture of (+)-trans-T and (−)-trans-T. The main metabolic pathways are O-demethylation and N-demethylation, producing trans-O-Desmethyltramadol (M1) and trans-N-desmethyltramadol (M2 ) enantiomers, respectively. The analgesic effect of T is related to the opioid activity of (+)-trans-T and (+)-M1 and to the monoaminergic action of (+/−)-trans-T. This is the first study using tandem mass spectrometry as a detection system for the simultaneous analysis of trans-T, M1, and M2 enantiomers. The analytes were resolved on a Chiralpak® AD column using hexane:ethanol (95.5:4.5, v/v) plus 0.1% diethylamine as the mobile phase. The quantitation limits were 0.5 ng/ml for trans-T and M1 and 0.1 ng/ml for M2 . The method developed and validated here was applied to a pharmacokinetic study in rats. Male Wistar rats (n = 6 at each time point) received a single oral dose of 20 mg/kg racemic trans-T. Blood samples were collected up to 12 h after drug administration. The kinetic disposition of trans-T and M2 was enantioselective (AUC(+)/(−) ratio = 4.16 and 6.36, respectively). The direction and extent of enantioselectivity in the pharmacokinetics of trans-T and M2 in rats were comparable to data previously reported for healthy volunteers, suggesting that rats are a suitable model for enantioselective studies of trans-T pharmacokinetics. Chirality, 2011. © 2010 Wiley-Liss, Inc.

Kari Laine - One of the best experts on this subject based on the ideXlab platform.

  • Effects of terbinafine and itraconazole on the pharmacokinetics of orally administered tramadol
    European Journal of Clinical Pharmacology, 2015
    Co-Authors: Tuukka Saarikoski, Teijo I. Saari, Nora M. Hagelberg, Janne T. Backman, Pertti J. Neuvonen, Mika Scheinin, Klaus T. Olkkola, Kari Laine
    Abstract:

    Background Tramadol is widely used for acute, chronic, and neuropathic pain. Its primary active metabolite is O-Desmethyltramadol (M1), which is mainly accountable for the μ-opioid receptor-related analgesic effect. Tramadol is metabolized to M1 mainly by cytochrome P450 (CYP)2D6 enzyme and to other metabolites by CYP3A4 and CYP2B6. We investigated the possible interaction of tramadol with the antifungal agents terbinafine (CYP2D6 inhibitor) and itraconazole (CYP3A4 inhibitor). Methods We used a randomized placebo-controlled crossover study design with 12 healthy subjects, of which 8 were extensive and 4 were ultrarapid CYP2D6 metabolizers. On the pretreatment day 4 with terbinafine (250 mg once daily), itraconazole (200 mg once daily) or placebo, subjects were given tramadol 50 mg orally. Plasma concentrations of tramadol and M1 were determined over 48 h and some pharmacodynamic effects over 12 h. Pharmacokinetic variables were calculated using standard non-compartmental methods. Results Terbinafine increased the area under plasma concentration–time curve (AUC_0-∞) of tramadol by 115 % and decreased the AUC_0-∞ of M1 by 64 % ( P  

  • Effects of terbinafine and itraconazole on the pharmacokinetics of orally administered tramadol
    European Journal of Clinical Pharmacology, 2015
    Co-Authors: Tuukka Saarikoski, Teijo I. Saari, Nora M. Hagelberg, Janne T. Backman, Pertti J. Neuvonen, Mika Scheinin, Klaus T. Olkkola, Kari Laine
    Abstract:

    Background Tramadol is widely used for acute, chronic, and neuropathic pain. Its primary active metabolite is O-Desmethyltramadol (M1), which is mainly accountable for the μ-opioid receptor-related analgesic effect. Tramadol is metabolized to M1 mainly by cytochrome P450 (CYP)2D6 enzyme and to other metabolites by CYP3A4 and CYP2B6. We investigated the possible interaction of tramadol with the antifungal agents terbinafine (CYP2D6 inhibitor) and itraconazole (CYP3A4 inhibitor).

Mohamad-samer Mouksassi - One of the best experts on this subject based on the ideXlab platform.

  • Population Pharmacokinetic/Pharmacodynamic Modeling of O-Desmethyltramadol in Young and Elderly Healthy Volunteers
    Drugs & Aging, 2019
    Co-Authors: Sybil Skinner Robertson, Mohamad-samer Mouksassi, France Varin
    Abstract:

    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/ f _m), volume of distribution ( V / f _m) and a sigmoid maximum effect ( E _max) model incorporating baseline ( E _0) 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 / f _m was 76% larger and CL/ f _m 16% slower. Baseline ( E _0) and sensitivity ( C _50) for pain tolerance were similar between young and elderly subjects. However, the E _max 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.

  • Population Pharmacokinetic/Pharmacodynamic Modeling of O -Desmethyltramadol in Young and Elderly Healthy Volunteers
    Drugs & Aging, 2019
    Co-Authors: Sybil Skinner Robertson, Mohamad-samer Mouksassi
    Abstract:

    Age-related changes in the concentration–effect relationship of (+)-O-desmethyl-tramadol [(+)-ODM], tramadol’s active metabolite, are not documented in the elderly. 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. 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. 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. 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.

  • Pharmacokinetics of Tramadol and O -Desmethyltramadol Enantiomers Following Administration of Extended-Release Tablets to Elderly and Young Subjects
    Drugs & Aging, 2015
    Co-Authors: Sybil Skinner-robertson, Caroline Fradette, Sylvie Bouchard, Mohamad-samer Mouksassi
    Abstract:

    Background Tramadol is frequently used in geriatric patients; however, pharmacokinetic (PK) publications on tramadol and O-Desmethyltramadol (ODM) in elderly patients are rare.