The Experts below are selected from a list of 189 Experts worldwide ranked by ideXlab platform
Megan A. Gibbs - One of the best experts on this subject based on the ideXlab platform.
-
Absolute Oral Bioavailability of Traxoprodil in Cytochrome P450 2D6 Extensive and Poor Metabolisers
Clinical Pharmacokinetics, 2006Co-Authors: Timothy J. Taylor, Kelly Diringer, Tanya Russell, Karthik Venkatakrishnan, Keith D. Wilner, Penelope Crownover, Lisa J. Benincosa, Megan A. GibbsAbstract:Background Traxoprodil, a substituted 4-phenylpiperidine, is an N -methyl-D-aspartate (NMDA) receptor antagonist that is selective for receptors containing the NR2B subunit. In vivo and in vitro studies examining the disposition of Traxoprodil have demonstrated that it is mainly metabolised by cytochrome P450 (CYP) 2D6, a major drug-metabolising enzyme that exhibits a genetic polymorphism. Objective To assess the single-dose absolute oral bioavailability of Traxoprodil in healthy male volunteers phenotyped as either CYP2D6 extensive or poor metabolisers. Methods This was an open-label, three-way crossover study. Traxoprodil was administered as a single dose orally in solution of 50, 100 and 300mg and intravenously as a constant rate 2-hour infusion of 50 and 100mg. CYP2D6 phenotype was assigned following single-dose dextromethorphan administration. Results In poor metabolisers (n = 6), oral bioavailability was ∼80% and was consistent with a liver extraction ratio of ∼20% (plasma clearance of ∼4 mL/min/ kg) indicating near complete absorption. Following intravenous administration, the mean volume of distribution at steady state (V_ss) was moderate (∼6.5 L/kg) and the mean elimination half-life (t_1/2) was ∼20 hours. Following oral administration the mean maximum plasma concentration (C_max) and area under the plasma concentration-time curve from time zero to infinity (AUC_∞) increased approximately proportionally with dose. In extensive metabolisers (n = 11), oral bioavailability was dose-dependent and nonlinear. At the 100mg dose, the absolute oral bioavailability was ∼39.5%. Overall, the oral bioavailability ranged from 22.8% to 62.1% and its estimation was confounded by large differences in plasma concentrations at oral doses without equivalent intravenous doses. Following intravenous administration, plasma clearance was high (∼27 mL/min/kg), the V_ss was moderate (∼4 L/Kg) and the t_1/2 was ∼2–4 hours. Following oral administration the C_max and AUC_∞ increased more than proportionally with dose. Apparent oral clearance decreased with increasing oral dose. However, t_1/2 was approximately the same at all doses (∼4 hours). Conclusion The pharmacokinetics of Traxoprodil were quite different in the two phenotypes. In extensive metabolisers, the oral bioavailability was nonlinear and dose-dependent, while in poor metabolisers, oral bioavailability appeared to be linear and dose-independent. Based on the pharmacokinetics in extensive and poor metabolisers, the nonlinear oral bioavailability in extensive metabolisers may be attributed to saturation of hepatic first-pass CYP2D6 metabolism. Thus, at a high oral dose, the impact of CYP2D6 metabolism on Traxoprodil pharmacokinetics is minimal.
-
Absolute oral bioavailability of Traxoprodil in cytochrome P450 2D6 extensive and poor metabolisers.
Clinical pharmacokinetics, 2006Co-Authors: Timothy J. Taylor, Kelly Diringer, Tanya Russell, Karthik Venkatakrishnan, Keith D. Wilner, Penelope Crownover, Lisa J. Benincosa, Megan A. GibbsAbstract:Background Traxoprodil, a substituted 4-phenylpiperidine, is an N-methyl-D-aspartate (NMDA) receptor antagonist that is selective for receptors containing the NR2B subunit. In vivo and in vitro studies examining the disposition of Traxoprodil have demonstrated that it is mainly metabolised by cytochrome P450 (CYP) 2D6, a major drug-metabolising enzyme that exhibits a genetic polymorphism.
Linda J Bristow - One of the best experts on this subject based on the ideXlab platform.
-
mapping the central effects of ketamine and Traxoprodil using pharmacological magnetic resonance imaging in awake rats
Journal of Psychopharmacology, 2018Co-Authors: Haiying Tang, Daniel W. Kukral, Matthew Fronheiser, Harold Malone, Adrienne Pena, Rick L. Pieschl, Kurex Sidik, Gabriel Tobon, Patrick L Chow, Linda J BristowAbstract:Major depressive disorder is a leading cause of disability globally. Improvements in the efficacy of antidepressant therapy are needed as a high proportion (>40%) of individuals with major depressive disorder fail to respond adequately to current treatments. The non-selective N-methyl-D-aspartate receptor channel blocker, (±)-ketamine, has been reported to produce a rapid and long-lasting antidepressant response in treatment-resistant major depressive disorder patients, which provides a unique opportunity for investigation of mechanisms that mediate its therapeutic effect. Efforts have also focused on the development of selective N-methyl-D-aspartate receptor subtype 2B antagonists which may retain antidepressant activity but have lower potential for dissociative/psychotomimetic effects. In the present study, we examined the central nervous system effects of acute, intravenous administration of (±)-ketamine or the N-methyl-D-aspartate receptor subtype 2B antagonist, Traxoprodil, in awake rats using pharmacological magnetic resonance imaging. The study contained five treatment groups: vehicle, 3 mg/kg (±)-ketamine, and three doses of Traxoprodil (0.3 mg/kg, 5 mg/kg, and 15 mg/kg). Non-linear model fitting was performed on the temporal hemodynamic pharmacological magnetic resonance imaging data to generate brain activation maps as well as regional responses based on blood oxygen level dependent signal changes for group analysis. Traxoprodil at 5 mg/kg and 15 mg/kg produced a dose-dependent pharmacological magnetic resonance imaging signal in rat forebrain regions with both doses achieving >80% N-methyl-D-aspartate receptor subtype 2B occupancy determined by ex vivo [3H]Ro 25-6981 binding. The middle dose of Traxoprodil (5 mg/kg) generated region-specific activations in medial prefrontal cortex, ventral orbital cortex, and anterior cingulate cortex whereas the high dose (15 mg/kg) produced a widespread pharmacological magnetic resonance imaging response in both cortical and subcortical brain regions which was similar to that produced by (±)-ketamine (3 mg/kg, intravenous).
-
The qEEG Signature of Selective NMDA NR2B Negative Allosteric Modulators; A Potential Translational Biomarker for Drug Development
PloS one, 2016Co-Authors: Deborah Keavy, Linda J Bristow, Digavalli V. Sivarao, Margaret Batchelder, Dalton King, Srinivasan Thangathirupathy, John E. Macor, Michael R. WeedAbstract:The antidepressant activity of the N-methyl-D-aspartate (NMDA) receptor channel blocker, ketamine, has led to the investigation of negative allosteric modulators (NAMs) selective for the NR2B receptor subtype. The clinical development of NR2B NAMs would benefit from a translational pharmacodynamic biomarker that demonstrates brain penetration and functional inhibition of NR2B receptors in preclinical species and humans. Quantitative electroencephalography (qEEG) is a translational measure that can be used to demonstrate pharmacodynamic effects across species. NMDA receptor channel blockers, such as ketamine and phencyclidine, increase the EEG gamma power band, which has been used as a pharmacodynamic biomarker in the development of NMDA receptor antagonists. However, detailed qEEG studies with ketamine or NR2B NAMs are lacking in nonhuman primates. The aim of the present study was to determine the effects on the qEEG power spectra of the NR2B NAMs Traxoprodil (CP-101,606) and BMT-108908 in nonhuman primates, and to compare them to the NMDA receptor channel blockers, ketamine and lanicemine. Cynomolgus monkeys were surgically implanted with EEG radio-telemetry transmitters, and qEEG was measured after vehicle or drug administration. The relative power for a number of frequency bands was determined. Ketamine and lanicemine increased relative gamma power, whereas the NR2B NAMs Traxoprodil and BMT-108908 had no effect. Robust decreases in beta power were elicited by ketamine, Traxoprodil and BMT-108908; and these agents also produced decreases in alpha power and increases in delta power at the doses tested. These results suggest that measurement of power spectra in the beta and delta bands may represent a translational pharmacodynamic biomarker to demonstrate functional effects of NR2B NAMs. The results of these studies may help guide the selection of qEEG measures that can be incorporated into early clinical evaluation of NR2B NAMs in healthy humans.
-
NR2b selective NAM’s elicit robust changes in beta 1 (13–19 Hz) qEEG in cynomolgus monkeys.
2016Co-Authors: Deborah Keavy, Linda J Bristow, Digavalli V. Sivarao, Margaret Batchelder, Dalton King, Srinivasan Thangathirupathy, John E. Macor, Michael R. WeedAbstract:Traxoprodil, 10 mg/kg IM (closed symbol) caused a reduction in beta 1 relative power and differs from vehicle (open symbol) at p < .05 level (Table 1). BMT-108908 3 mg/kg IV (closed symbol) decreased beta 1 band and differs from vehicle (open symbol) at p < .001 (Table 1).
-
NR2b selective NAM’s have no effect on gamma (30–55 Hz) qEEG in cynomolgus monkeys.
2016Co-Authors: Deborah Keavy, Linda J Bristow, Digavalli V. Sivarao, Margaret Batchelder, Dalton King, Srinivasan Thangathirupathy, John E. Macor, Michael R. WeedAbstract:Y-axis is relative power in gamma (30–55 Hz) frequency band of the EEG power spectrum. X-axis is time after IM or IV administration. Results are the mean ± SEM (N = 5–6). Traxoprodil, 10 mg/kg IM and BMT-108908 3 mg/kg IV (closed symbol) had no effect on gamma, p>.05 (Table 1).
Carlos Fernando Mello - One of the best experts on this subject based on the ideXlab platform.
-
Inhibition of the polyamine system counteracts β-amyloid peptide-induced memory impairment in mice: involvement of extrasynaptic NMDA receptors.
PloS one, 2014Co-Authors: Guilherme M. Gomes, Carlos Fernando Mello, Gerusa Duarte Dalmolin, Julia Bär, Anna Karpova, Michael R. Kreutz, Maribel Antonello RubinAbstract:In Alzheimer's disease (AD), the β-amyloid peptide (Aβ) has been causally linked to synaptic dysfunction and cognitive impairment. Several studies have shown that N-Methyl-D-Aspartate receptors (NMDAR) activation is involved in the detrimental actions of Aβ. Polyamines, like spermidine and spermine, are positive modulators of NMDAR function and it has been shown that their levels are regulated by Aβ. In this study we show here that interruption of NMDAR modulation by polyamines through blockade of its binding site at NMDAR by arcaine (0.02 nmol/site), or inhibition of polyamine synthesis by DFMO (2.7 nmol/site), reverses Aβ25–35-induced memory impairment in mice in a novel object recognition task. Incubation of hippocampal cell cultures with Aβ25–35 (10 µM) significantly increased the nuclear accumulation of Jacob, which is a hallmark of NMDAR activation. The Aβ-induced nuclear translocation of Jacob was blocked upon application of Traxoprodil (4 nM), arcaine (4 µM) or DFMO (5 µM), suggesting that activation of the polyamine binding site at NMDAR located probably at extrasynaptic sites might underlie the cognitive deficits of Aβ25–35-treated mice. Extrasynaptic NMDAR activation in primary neurons results in a stripping of synaptic contacts and simplification of neuronal cytoarchitecture. Aβ25–35 application in hippocampal primary cell cultures reduced dendritic spine density and induced alterations on spine morphology. Application of Traxoprodil (4 nM), arcaine (4 µM) or DFMO (5 µM) reversed these effects of Aβ25–35. Taken together these data provide evidence that polyamine modulation of extrasynaptic NMDAR signaling might be involved in Aβ pathology.
-
Traxoprodil (B, C), arcaine (D, E) and DFMO (F, G) restore memory of Aβ25–35-injected mice, in the novel object recognition task.
2014Co-Authors: Guilherme Monteiro Gomes, Carlos Fernando Mello, Gerusa Duarte Dalmolin, Julia Bär, Anna Karpova, Michael R. Kreutz, Maribel Antonello RubinAbstract:(A) Experimental schedule, i.c.v., intracerebroventricular. Traxoprodil and arcaine were administered immediately after training. DFMO was administered 1 hour prior training. Data shown as mean +S.E.M. N = 3 = –5 animals per group for B, D, F. N = 5–9 animals per group for C, E, G. *P
-
Spermidine and Aβ-25–35 induces nuclear Jacob accumulation of hippocampal neurons through stimulation of extrasynaptic NMDARs.
2014Co-Authors: Guilherme Monteiro Gomes, Carlos Fernando Mello, Gerusa Duarte Dalmolin, Julia Bär, Anna Karpova, Michael R. Kreutz, Maribel Antonello RubinAbstract:NMDA (200 µM) and spermidine (400 µM) increases nuclear Jacob localization (A, E). Aβ25–35-induced Jacob translocation to the nucleus it is blocked by co-incubation with Traxoprodil (4 nM) (B, F), or arcaine (C, G). Incubation of DFMO (5 µM) 10 min prior addition of Aβ25–35, also block Jacob translocation (D, H). Scale bars represents 10 µm. Data shown as mean + S.E.M., N: 17–24 cells per group. **p
-
Traxoprodil (B, C), arcaine (D, E) or DFMO (F, G) rescues dendritic spine number and morphology changes induced by Aβ25–35 in hippocampal neuron cultures.
2014Co-Authors: Guilherme Monteiro Gomes, Carlos Fernando Mello, Gerusa Duarte Dalmolin, Julia Bär, Anna Karpova, Michael R. Kreutz, Maribel Antonello RubinAbstract:(A) Representative micrographs depicting GFP-filled dendrites. Cells were incubated with Aβ25–35 for 24 hours and Traxoprodil (4 nM), arcaine (4 µM) or DFMO (5 µM) were added 2 hours prior fixation. Spine density and morphology analysis was performed in 20 µm dendrite segments. Spines were classified according to their morphology. Scale bar represent 5 µm. In each experiment 30 to 48 dendritic segments were analyzed Data shown as mean + S.E.M. *P
-
Traxoprodil decreases pentylenetetrazol-induced seizures
Epilepsy Research, 2012Co-Authors: Ana Paula Naspolini, Felipe Villa Martignoni, Ariane Rubin Cocco, Mauro Schneider Oliveira, Ana Flávia Furian, Leonardo Magno Rambo, Maribel Antonello Rubin, Susan Barron, Carlos Fernando MelloAbstract:Summary Polyamines, including spermidine, facilitate seizures by positively modulating N-methyl- d -aspartate receptors (NMDAr). Although NMDAr antagonists decrease seizures, it remains to be determined whether Traxoprodil, a selective antagonist at the NR2B subunit of the NMDAr, decreases seizures and whether spermidine facilitates pentylenetetrazol (PTZ)-induced seizures. Adult male Wistar rats were injected in the lateral ventricle with 0.9% NaCl (1 μl, i.c.v.), spermidine (0.02, 0.2 or 2 nmol/site, i.c.v.) or Traxoprodil (0.2, 2 or 20 nmol, i.c.v.) and with PTZ (35 or 70 mg/kg, i.p.). The effect of orally administered Traxoprodil (60 mg/kg, p.o.) on seizures was also investigated. Latencies to clonic and generalized seizures, as well the total time spent in seizures were recorded by behavioral and electrographic methods (EEG). Spermidine (2 nmol/site; i.c.v.) facilitated the seizures induced by a sub-threshold dose of PTZ (35 mg/kg; i.p.), but did not alter seizure activity induced by a convulsant dose of PTZ (70 mg/kg; i.p.). Traxoprodil (20 nmol i.c.v.) increased the latency to generalized tonic–clonic seizures induced by PTZ (70 mg/kg; i.p.). Traxoprodil (60 mg/kg, p.o.) increased the latency to clonic and generalized seizures, and decreased the total time spent in seizures. These results support the role for the NR2B subunit in PTZ-induced seizures.
Maribel Antonello Rubin - One of the best experts on this subject based on the ideXlab platform.
-
Inhibition of the Polyamine System Counteracts b- Amyloid Peptide-Induced Memory Impairment in Mice: Involvement of Extrasynaptic NMDA Receptors
2016Co-Authors: Guilherme Monteiro Gomes, Gerusa Duarte Dalmolin, Anna Karpova, Michael R. Kreutz, O Mello, Maribel Antonello RubinAbstract:In Alzheimer’s disease (AD), the b-amyloid peptide (Ab) has been causally linked to synaptic dysfunction and cognitive impairment. Several studies have shown that N-Methyl-D-Aspartate receptors (NMDAR) activation is involved in the detrimental actions of Ab. Polyamines, like spermidine and spermine, are positive modulators of NMDAR function and it has been shown that their levels are regulated by Ab. In this study we show here that interruption of NMDAR modulation by polyamines through blockade of its binding site at NMDAR by arcaine (0.02 nmol/site), or inhibition of polyamine synthesis by DFMO (2.7 nmol/site), reverses Ab25–35-induced memory impairment in mice in a novel object recognition task. Incubation of hippocampal cell cultures with Ab25–35 (10 mM) significantly increased the nuclear accumulation of Jacob, which is a hallmark of NMDAR activation. The Ab-induced nuclear translocation of Jacob was blocked upon application of Traxoprodil (4 nM), arcaine (4 mM) or DFMO (5 mM), suggesting that activation of the polyamine binding site at NMDAR located probably at extrasynaptic sites might underlie the cognitive deficits of Ab25–35-treated mice. Extrasynaptic NMDAR activation in primary neurons results in a stripping of synaptic contacts and simplification of neuronal cytoarchitecture. Ab25–35 application in hippocampal primary cell cultures reduced dendritic spine density and induced alterations on spine morphology. Application of Traxoprodil (4 nM), arcaine (4 mM) or DFMO (5 mM) reversed these effects of Ab25–35. Taken together these data provide evidence that polyamine modulation of extrasynaptic NMDAR signaling might be involved i
-
Inhibition of the polyamine system counteracts β-amyloid peptide-induced memory impairment in mice: involvement of extrasynaptic NMDA receptors.
PloS one, 2014Co-Authors: Guilherme M. Gomes, Carlos Fernando Mello, Gerusa Duarte Dalmolin, Julia Bär, Anna Karpova, Michael R. Kreutz, Maribel Antonello RubinAbstract:In Alzheimer's disease (AD), the β-amyloid peptide (Aβ) has been causally linked to synaptic dysfunction and cognitive impairment. Several studies have shown that N-Methyl-D-Aspartate receptors (NMDAR) activation is involved in the detrimental actions of Aβ. Polyamines, like spermidine and spermine, are positive modulators of NMDAR function and it has been shown that their levels are regulated by Aβ. In this study we show here that interruption of NMDAR modulation by polyamines through blockade of its binding site at NMDAR by arcaine (0.02 nmol/site), or inhibition of polyamine synthesis by DFMO (2.7 nmol/site), reverses Aβ25–35-induced memory impairment in mice in a novel object recognition task. Incubation of hippocampal cell cultures with Aβ25–35 (10 µM) significantly increased the nuclear accumulation of Jacob, which is a hallmark of NMDAR activation. The Aβ-induced nuclear translocation of Jacob was blocked upon application of Traxoprodil (4 nM), arcaine (4 µM) or DFMO (5 µM), suggesting that activation of the polyamine binding site at NMDAR located probably at extrasynaptic sites might underlie the cognitive deficits of Aβ25–35-treated mice. Extrasynaptic NMDAR activation in primary neurons results in a stripping of synaptic contacts and simplification of neuronal cytoarchitecture. Aβ25–35 application in hippocampal primary cell cultures reduced dendritic spine density and induced alterations on spine morphology. Application of Traxoprodil (4 nM), arcaine (4 µM) or DFMO (5 µM) reversed these effects of Aβ25–35. Taken together these data provide evidence that polyamine modulation of extrasynaptic NMDAR signaling might be involved in Aβ pathology.
-
Traxoprodil (B, C), arcaine (D, E) and DFMO (F, G) restore memory of Aβ25–35-injected mice, in the novel object recognition task.
2014Co-Authors: Guilherme Monteiro Gomes, Carlos Fernando Mello, Gerusa Duarte Dalmolin, Julia Bär, Anna Karpova, Michael R. Kreutz, Maribel Antonello RubinAbstract:(A) Experimental schedule, i.c.v., intracerebroventricular. Traxoprodil and arcaine were administered immediately after training. DFMO was administered 1 hour prior training. Data shown as mean +S.E.M. N = 3 = –5 animals per group for B, D, F. N = 5–9 animals per group for C, E, G. *P
-
Spermidine and Aβ-25–35 induces nuclear Jacob accumulation of hippocampal neurons through stimulation of extrasynaptic NMDARs.
2014Co-Authors: Guilherme Monteiro Gomes, Carlos Fernando Mello, Gerusa Duarte Dalmolin, Julia Bär, Anna Karpova, Michael R. Kreutz, Maribel Antonello RubinAbstract:NMDA (200 µM) and spermidine (400 µM) increases nuclear Jacob localization (A, E). Aβ25–35-induced Jacob translocation to the nucleus it is blocked by co-incubation with Traxoprodil (4 nM) (B, F), or arcaine (C, G). Incubation of DFMO (5 µM) 10 min prior addition of Aβ25–35, also block Jacob translocation (D, H). Scale bars represents 10 µm. Data shown as mean + S.E.M., N: 17–24 cells per group. **p
-
Traxoprodil (B, C), arcaine (D, E) or DFMO (F, G) rescues dendritic spine number and morphology changes induced by Aβ25–35 in hippocampal neuron cultures.
2014Co-Authors: Guilherme Monteiro Gomes, Carlos Fernando Mello, Gerusa Duarte Dalmolin, Julia Bär, Anna Karpova, Michael R. Kreutz, Maribel Antonello RubinAbstract:(A) Representative micrographs depicting GFP-filled dendrites. Cells were incubated with Aβ25–35 for 24 hours and Traxoprodil (4 nM), arcaine (4 µM) or DFMO (5 µM) were added 2 hours prior fixation. Spine density and morphology analysis was performed in 20 µm dendrite segments. Spines were classified according to their morphology. Scale bar represent 5 µm. In each experiment 30 to 48 dendritic segments were analyzed Data shown as mean + S.E.M. *P
Timothy J. Taylor - One of the best experts on this subject based on the ideXlab platform.
-
Absolute Oral Bioavailability of Traxoprodil in Cytochrome P450 2D6 Extensive and Poor Metabolisers
Clinical Pharmacokinetics, 2006Co-Authors: Timothy J. Taylor, Kelly Diringer, Tanya Russell, Karthik Venkatakrishnan, Keith D. Wilner, Penelope Crownover, Lisa J. Benincosa, Megan A. GibbsAbstract:Background Traxoprodil, a substituted 4-phenylpiperidine, is an N -methyl-D-aspartate (NMDA) receptor antagonist that is selective for receptors containing the NR2B subunit. In vivo and in vitro studies examining the disposition of Traxoprodil have demonstrated that it is mainly metabolised by cytochrome P450 (CYP) 2D6, a major drug-metabolising enzyme that exhibits a genetic polymorphism. Objective To assess the single-dose absolute oral bioavailability of Traxoprodil in healthy male volunteers phenotyped as either CYP2D6 extensive or poor metabolisers. Methods This was an open-label, three-way crossover study. Traxoprodil was administered as a single dose orally in solution of 50, 100 and 300mg and intravenously as a constant rate 2-hour infusion of 50 and 100mg. CYP2D6 phenotype was assigned following single-dose dextromethorphan administration. Results In poor metabolisers (n = 6), oral bioavailability was ∼80% and was consistent with a liver extraction ratio of ∼20% (plasma clearance of ∼4 mL/min/ kg) indicating near complete absorption. Following intravenous administration, the mean volume of distribution at steady state (V_ss) was moderate (∼6.5 L/kg) and the mean elimination half-life (t_1/2) was ∼20 hours. Following oral administration the mean maximum plasma concentration (C_max) and area under the plasma concentration-time curve from time zero to infinity (AUC_∞) increased approximately proportionally with dose. In extensive metabolisers (n = 11), oral bioavailability was dose-dependent and nonlinear. At the 100mg dose, the absolute oral bioavailability was ∼39.5%. Overall, the oral bioavailability ranged from 22.8% to 62.1% and its estimation was confounded by large differences in plasma concentrations at oral doses without equivalent intravenous doses. Following intravenous administration, plasma clearance was high (∼27 mL/min/kg), the V_ss was moderate (∼4 L/Kg) and the t_1/2 was ∼2–4 hours. Following oral administration the C_max and AUC_∞ increased more than proportionally with dose. Apparent oral clearance decreased with increasing oral dose. However, t_1/2 was approximately the same at all doses (∼4 hours). Conclusion The pharmacokinetics of Traxoprodil were quite different in the two phenotypes. In extensive metabolisers, the oral bioavailability was nonlinear and dose-dependent, while in poor metabolisers, oral bioavailability appeared to be linear and dose-independent. Based on the pharmacokinetics in extensive and poor metabolisers, the nonlinear oral bioavailability in extensive metabolisers may be attributed to saturation of hepatic first-pass CYP2D6 metabolism. Thus, at a high oral dose, the impact of CYP2D6 metabolism on Traxoprodil pharmacokinetics is minimal.
-
Absolute oral bioavailability of Traxoprodil in cytochrome P450 2D6 extensive and poor metabolisers.
Clinical pharmacokinetics, 2006Co-Authors: Timothy J. Taylor, Kelly Diringer, Tanya Russell, Karthik Venkatakrishnan, Keith D. Wilner, Penelope Crownover, Lisa J. Benincosa, Megan A. GibbsAbstract:Background Traxoprodil, a substituted 4-phenylpiperidine, is an N-methyl-D-aspartate (NMDA) receptor antagonist that is selective for receptors containing the NR2B subunit. In vivo and in vitro studies examining the disposition of Traxoprodil have demonstrated that it is mainly metabolised by cytochrome P450 (CYP) 2D6, a major drug-metabolising enzyme that exhibits a genetic polymorphism.
