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Stephen D. Hall - One of the best experts on this subject based on the ideXlab platform.
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Dextromethorphan to dextrorphan urinary metabolic ratio does not reflect Dextromethorphan oral clearance
Drug Metabolism and Disposition, 2005Co-Authors: S Borges, Mitchell A. Hamman, Stephen D. Hall, David R Jones, Lang Li, Christopher J GorskiAbstract:Dextromethorphan urinary metabolic ratio is widely used to determine the CYP2D6 phenotype, but its utility to reflect subtle differences in catalytic activity is unclear. We evaluated the capability of Dextromethorphan urinary metabolic ratio to predict Dextromethorphan oral clearance as a measure of CYP2D6 activity. Data from 10 healthy extensive metabolizers of CYP2D6 were given 30 mg of Dextromethorphan hydrobromide orally on two occasions. Blood and urine samples were collected for 72 h. Dextromethorphan and dextrorphan were determined in urine by high-performance liquid chromatography with fluorescence detection and in serum by liquid chromatography-mass spectrometry. The urinary metabolic ratio was very weakly correlated with Dextromethorphan oral clearance (r = 0.24; p = 0.04). In contrast, the Dextromethorphan oral clearance was highly correlated with the Dextromethorphan to dextrorphan area under the concentration-time curve ratio (r = 0.84; p = 0.005) and the 3-h (r = 0.60; p = 0.003), 4-h (r = 0.72, p
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characterization of Dextromethorphan n demethylation by human liver microsomes contribution of the cytochrome p450 3a cyp3a subfamily
Biochemical Pharmacology, 1994Co-Authors: Christopher J Gorski, Steven A Wrighton, Stephen D. Hall, David R JonesAbstract:In an effort to identify the human cytochromes P450 involved in the N-demethylation of Dextromethorphan, the kinetics of 3-methoxymorphinan formation were studied in microsomal enzyme systems. Under initial rate conditions, 3-methoxymorphinan formation demonstrated single enzyme Michaelis-Menten kinetics using microsomes obtained from three human livers (Km: 0.52–0.71 mM; Vmax: 375–812 pmol/mg protein/min). B-lymphoblastoid cells expressing CYP3A4 incubated with 0.4 mM Dextromethorphan catalyzed the formation of 3-methoxymorphinan at a rate of 22 pmol product/mg protein/min. Midazolam, a prototypic substrate for CYP3A4 and CYP3A5, competitively inhibited Dextromethorphan N-demethylation by two human liver microsomal samples with Ki values of 46 ± 10 and 63 ± 8 μM. At a Dextromethorphan concentration of 0.4 mM, gestodene (100 μM) inhibited 3-methoxymorphinan formation by approximately 50%. Immunoinhibition of dextro-methorphan N-demethylation using rabbit anti-CYP3A4 antibodies resulted in a 60% decrease in 3-methoxymorphinan formation at a Dextromethorphan concentration of 0.4 mM. Additional inhibition studies using furafylline, coumarin, sulfaphenazole, mephenytoin, quinidine, and diethyldithiocarbamic acid, which are selective inhibitors of CYP1A2, CYP2A6, CYP2C8/9, CYP2Cmp, CYP2D6, and CYP2E1, respectively, demonstrated no substantial inhibition of Dextromethorphan N-demethylation. Correlation analysis was performed using the rate of 3-methoxymorphinan formation at a concentration of 1mM Dextromethorphan and immunoquantified levels of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 and their associated characteristic catalytic activities. A significant correlation was observed between Dextromethorphan N-demethylase activity and midazolam 1'- and 4-hydroxylase activity (r2 = 0.77 and 0.69 respectively, N = 19, P < 0.01); the exclusion of those samples containing both CYP3A4 and CYP3A5 increased the correlation significantly (r2 = 0.87 and 0.91 respectively, N = 12, P < 0.01). In the absence of CYP3A5, a significant correlation was observed between 3-methoxymorphinan formation and the sample's erythromycin N-demethylase activity (r2= 0.94, N = 12, P < 0.01), testosterone 6 β-hydroxylase activity (r2 = 0.96, N = 7, P < 0.01) and relative immunoquantified levels of CYP3A4 (r2 = 0.96, N = 12, P < 0.01). Inclusion of those samples expressing CYP3A5 in addition to CYP3A4 reduced the magnitude of the observed correlation. No significant correlation between 3-methoxymorphinan formation and the sample's relative immunoquantified levels of or form-selective activity associated with CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19 (or CYP2Cmp), CYP2D6, and CYP2E1 was observed. In conclusion, Dextromethorphan N-demethylation appears to be catalyzed primarily by CYP3A4 and to a lesser extent by CYP3A5 in vitro in humans. Thus, the administration of Dextromethorphan to human volunteers may provide a means of simultaneously phenotyping the in vivo activity of CYP2D6 and CYP3A.
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characterization of Dextromethorphan n demethylation by human liver microsomes contribution of the cytochrome p450 3a cyp3a subfamily
Biochemical Pharmacology, 1994Co-Authors: Christopher J Gorski, Steven A Wrighton, Stephen D. Hall, David R JonesAbstract:In an effort to identify the human cytochromes P450 involved in the N-demethylation of Dextromethorphan, the kinetics of 3-methoxymorphinan formation were studied in microsomal enzyme systems. Under initial rate conditions, 3-methoxymorphinan formation demonstrated single enzyme Michaelis-Menten kinetics using microsomes obtained from three human livers (Km: 0.52-0.71 mM; Vmax: 375-812 pmol/mg protein/min). B-lymphoblastoid cells expressing CYP3A4 incubated with 0.4 mM Dextromethorphan catalyzed the formation of 3-methoxymorphinan at a rate of 22 pmol product/mg protein/min. Midazolam, a prototypic substrate for CYP3A4 and CYP3A5, competitively inhibited Dextromethorphan N-demethylation by two human liver microsomal samples with Ki values of 46 +/- 10 and 63 +/- 8 microM. At a Dextromethorphan concentration of 0.4 mM, gestodene (100 microM) inhibited 3-methoxymorphinan formation by approximately 50%. Immunoinhibition of Dextromethorphan N-demethylation using rabbit anti-CYP3A4 antibodies resulted in a 60% decrease in 3-methoxymorphinan formation at a Dextromethorphan concentration of 0.4 mM. Additional inhibition studies using furafylline, coumarin, sulfaphenazole, mephenytoin, quinidine, and diethyldithiocarbamic acid, which are selective inhibitors of CYP1A2, CYP2A6, CYP2C8/9, CYP2Cmp, CYP2D6, and CYP2E1, respectively, demonstrated no substantial inhibition of Dextromethorphan N-demethylation. Correlation analysis was performed using the rate of 3-methoxymorphinan formation at a concentration of 1 mM Dextromethorphan and immunoquantified levels of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 and their associated characteristic catalytic activities. A significant correlation was observed between Dextromethorphan N-demethylase activity and midazolam 1'- and 4-hydroxylase activity (r2 = 0.77 and 0.69 respectively, N = 19, P < 0.01); the exclusion of those samples containing both CYP3A4 and CYP3A5 increased the correlation significantly (r2 = 0.87 and 0.91 respectively, N = 12, P < 0.01). In the absence of CYP3A5, a significant correlation was observed between 3-methoxymorphinan formation and the sample's erythromycin N-demethylase activity (r2 = 0.94, N = 12, P < 0.01), testosterone 6 beta-hydroxylase activity (r2 = 0.96, N = 7, P < 0.01) and relative immunoquantified levels of CYP3A4 (r2 = 0.96, N = 12, P < 0.01). Inclusion of those samples expressing CYP3A5 in addition to CYP3A4 reduced the magnitude of the observed correlation. No significant correlation between 3-methoxymorphinan formation and the sample's relative immunoquantified levels of or form-selective activity associated with CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19 (or CYP2Cmp), CYP2D6, and CYP2E1 was observed. In conclusion, Dextromethorphan N-demethylation appears to be catalyzed primarily by CYP3A4 and to a lesser extent by CYP3A5 in vitro in humans.(ABSTRACT TRUNCATED AT 400 WORDS)
Christopher J Gorski - One of the best experts on this subject based on the ideXlab platform.
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Dextromethorphan to dextrorphan urinary metabolic ratio does not reflect Dextromethorphan oral clearance
Drug Metabolism and Disposition, 2005Co-Authors: S Borges, Mitchell A. Hamman, Stephen D. Hall, David R Jones, Lang Li, Christopher J GorskiAbstract:Dextromethorphan urinary metabolic ratio is widely used to determine the CYP2D6 phenotype, but its utility to reflect subtle differences in catalytic activity is unclear. We evaluated the capability of Dextromethorphan urinary metabolic ratio to predict Dextromethorphan oral clearance as a measure of CYP2D6 activity. Data from 10 healthy extensive metabolizers of CYP2D6 were given 30 mg of Dextromethorphan hydrobromide orally on two occasions. Blood and urine samples were collected for 72 h. Dextromethorphan and dextrorphan were determined in urine by high-performance liquid chromatography with fluorescence detection and in serum by liquid chromatography-mass spectrometry. The urinary metabolic ratio was very weakly correlated with Dextromethorphan oral clearance (r = 0.24; p = 0.04). In contrast, the Dextromethorphan oral clearance was highly correlated with the Dextromethorphan to dextrorphan area under the concentration-time curve ratio (r = 0.84; p = 0.005) and the 3-h (r = 0.60; p = 0.003), 4-h (r = 0.72, p
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characterization of Dextromethorphan n demethylation by human liver microsomes contribution of the cytochrome p450 3a cyp3a subfamily
Biochemical Pharmacology, 1994Co-Authors: Christopher J Gorski, Steven A Wrighton, Stephen D. Hall, David R JonesAbstract:In an effort to identify the human cytochromes P450 involved in the N-demethylation of Dextromethorphan, the kinetics of 3-methoxymorphinan formation were studied in microsomal enzyme systems. Under initial rate conditions, 3-methoxymorphinan formation demonstrated single enzyme Michaelis-Menten kinetics using microsomes obtained from three human livers (Km: 0.52–0.71 mM; Vmax: 375–812 pmol/mg protein/min). B-lymphoblastoid cells expressing CYP3A4 incubated with 0.4 mM Dextromethorphan catalyzed the formation of 3-methoxymorphinan at a rate of 22 pmol product/mg protein/min. Midazolam, a prototypic substrate for CYP3A4 and CYP3A5, competitively inhibited Dextromethorphan N-demethylation by two human liver microsomal samples with Ki values of 46 ± 10 and 63 ± 8 μM. At a Dextromethorphan concentration of 0.4 mM, gestodene (100 μM) inhibited 3-methoxymorphinan formation by approximately 50%. Immunoinhibition of dextro-methorphan N-demethylation using rabbit anti-CYP3A4 antibodies resulted in a 60% decrease in 3-methoxymorphinan formation at a Dextromethorphan concentration of 0.4 mM. Additional inhibition studies using furafylline, coumarin, sulfaphenazole, mephenytoin, quinidine, and diethyldithiocarbamic acid, which are selective inhibitors of CYP1A2, CYP2A6, CYP2C8/9, CYP2Cmp, CYP2D6, and CYP2E1, respectively, demonstrated no substantial inhibition of Dextromethorphan N-demethylation. Correlation analysis was performed using the rate of 3-methoxymorphinan formation at a concentration of 1mM Dextromethorphan and immunoquantified levels of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 and their associated characteristic catalytic activities. A significant correlation was observed between Dextromethorphan N-demethylase activity and midazolam 1'- and 4-hydroxylase activity (r2 = 0.77 and 0.69 respectively, N = 19, P < 0.01); the exclusion of those samples containing both CYP3A4 and CYP3A5 increased the correlation significantly (r2 = 0.87 and 0.91 respectively, N = 12, P < 0.01). In the absence of CYP3A5, a significant correlation was observed between 3-methoxymorphinan formation and the sample's erythromycin N-demethylase activity (r2= 0.94, N = 12, P < 0.01), testosterone 6 β-hydroxylase activity (r2 = 0.96, N = 7, P < 0.01) and relative immunoquantified levels of CYP3A4 (r2 = 0.96, N = 12, P < 0.01). Inclusion of those samples expressing CYP3A5 in addition to CYP3A4 reduced the magnitude of the observed correlation. No significant correlation between 3-methoxymorphinan formation and the sample's relative immunoquantified levels of or form-selective activity associated with CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19 (or CYP2Cmp), CYP2D6, and CYP2E1 was observed. In conclusion, Dextromethorphan N-demethylation appears to be catalyzed primarily by CYP3A4 and to a lesser extent by CYP3A5 in vitro in humans. Thus, the administration of Dextromethorphan to human volunteers may provide a means of simultaneously phenotyping the in vivo activity of CYP2D6 and CYP3A.
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characterization of Dextromethorphan n demethylation by human liver microsomes contribution of the cytochrome p450 3a cyp3a subfamily
Biochemical Pharmacology, 1994Co-Authors: Christopher J Gorski, Steven A Wrighton, Stephen D. Hall, David R JonesAbstract:In an effort to identify the human cytochromes P450 involved in the N-demethylation of Dextromethorphan, the kinetics of 3-methoxymorphinan formation were studied in microsomal enzyme systems. Under initial rate conditions, 3-methoxymorphinan formation demonstrated single enzyme Michaelis-Menten kinetics using microsomes obtained from three human livers (Km: 0.52-0.71 mM; Vmax: 375-812 pmol/mg protein/min). B-lymphoblastoid cells expressing CYP3A4 incubated with 0.4 mM Dextromethorphan catalyzed the formation of 3-methoxymorphinan at a rate of 22 pmol product/mg protein/min. Midazolam, a prototypic substrate for CYP3A4 and CYP3A5, competitively inhibited Dextromethorphan N-demethylation by two human liver microsomal samples with Ki values of 46 +/- 10 and 63 +/- 8 microM. At a Dextromethorphan concentration of 0.4 mM, gestodene (100 microM) inhibited 3-methoxymorphinan formation by approximately 50%. Immunoinhibition of Dextromethorphan N-demethylation using rabbit anti-CYP3A4 antibodies resulted in a 60% decrease in 3-methoxymorphinan formation at a Dextromethorphan concentration of 0.4 mM. Additional inhibition studies using furafylline, coumarin, sulfaphenazole, mephenytoin, quinidine, and diethyldithiocarbamic acid, which are selective inhibitors of CYP1A2, CYP2A6, CYP2C8/9, CYP2Cmp, CYP2D6, and CYP2E1, respectively, demonstrated no substantial inhibition of Dextromethorphan N-demethylation. Correlation analysis was performed using the rate of 3-methoxymorphinan formation at a concentration of 1 mM Dextromethorphan and immunoquantified levels of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 and their associated characteristic catalytic activities. A significant correlation was observed between Dextromethorphan N-demethylase activity and midazolam 1'- and 4-hydroxylase activity (r2 = 0.77 and 0.69 respectively, N = 19, P < 0.01); the exclusion of those samples containing both CYP3A4 and CYP3A5 increased the correlation significantly (r2 = 0.87 and 0.91 respectively, N = 12, P < 0.01). In the absence of CYP3A5, a significant correlation was observed between 3-methoxymorphinan formation and the sample's erythromycin N-demethylase activity (r2 = 0.94, N = 12, P < 0.01), testosterone 6 beta-hydroxylase activity (r2 = 0.96, N = 7, P < 0.01) and relative immunoquantified levels of CYP3A4 (r2 = 0.96, N = 12, P < 0.01). Inclusion of those samples expressing CYP3A5 in addition to CYP3A4 reduced the magnitude of the observed correlation. No significant correlation between 3-methoxymorphinan formation and the sample's relative immunoquantified levels of or form-selective activity associated with CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19 (or CYP2Cmp), CYP2D6, and CYP2E1 was observed. In conclusion, Dextromethorphan N-demethylation appears to be catalyzed primarily by CYP3A4 and to a lesser extent by CYP3A5 in vitro in humans.(ABSTRACT TRUNCATED AT 400 WORDS)
Mitchell B Max - One of the best experts on this subject based on the ideXlab platform.
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Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia efficacy and dose response trials
Anesthesiology, 2002Co-Authors: Christine N Sang, Susan Booher, Ian Gilron, Suzan Parada, Mitchell B MaxAbstract:Background There are few repeated dose-controlled trials of N-methyl-d-aspartate glutamate receptor antagonists in patients with neuropathic pain. The authors sought to evaluate two low-affinity N-methyl-d-aspartate antagonists using a novel two-stage design. Methods The authors studied patients with painful diabetic neuropathy (DN) and postherpetic neuralgia (PHN) in two crossover trials: (1) efficacy trial (Dextromethorphan vs. memantine vs. active placebo [lorazepam]) and (2) dose-response trial of the preferred active drug in responders from the first study (0% vs. 25% vs. 50% vs. 100% of each patient's maximally tolerated dose). Pain intensity was measured on a 20-point scale. Results Nineteen of 23 DN patients and 17 of 21 PHN patients completed the efficacy trial. Median doses for DN and PHN were 400 and 400 mg/day Dextromethorphan, 55 and 35 mg/day memantine, and 1.8 and 1.2 mg/day lorazepam. In the efficacy trial, among patients with DN, Dextromethorphan reduced pain intensity by a mean of 33% from baseline, memantine reduced pain intensity by a mean of 17%, and lorazepam reduced pain intensity by a mean of 16%; the proportions of subjects achieving greater than moderate pain relief were 68% with Dextromethorphan, 47% with memantine, and 37% with lorazepam. Mean reductions in pain intensity in patients with PHN were 6% with Dextromethorphan, 2% with memantine, and 0% with lorazepam. No comparison with placebo reached statistical significance in the efficacy trial. In the 10 DN subjects who responded to Dextromethorphan, there was a significant dose-response effect on pain intensity (P = 0.035), with the highest dose significantly better than that of lorazepam (P = 0.03). Conclusions Dextromethorphan is effective in a dose-related fashion in selected patients with DN. This was not true of PHN, suggesting a difference in pain mechanisms. Selective approaches to pain-relevant N-methyl-d-aspartate receptors are warranted.
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high dose oral Dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia
Neurology, 1997Co-Authors: Kristine A Nelson, Karen M Park, Elaine Robinovitz, Constantine Tsigos, Mitchell B MaxAbstract:N-methyl-D-aspartate (NMDA) receptor antagonists relieve neuropathic pain in animal models, but side effects of dissociative anesthetic channel blockers, such as ketamine, have discouraged clinical application. Based on the hypothesis that low-affinity NMDA channel blockers might have a better therapeutic ratio, we carried out two randomized, double-blind, crossover trials comparing six weeks of oral Dextromethorphan to placebo in two groups, made up of 14 patients with painful distal symmetrical diabetic neuropathy and 18 with postherpetic neuralgia. Thirteen patients with each diagnosis completed the comparison. Dosage was titrated in each patient to the highest level reached without disrupting normal activities; mean doses were 381 mglday in diabetics and 439 mglday in postherpetic neuralgia patients. In diabetic neuropathy, Dextromethorphan decreased pain by a mean of 24% (95% CI: 6% to 42%, p = 0.011, relative to placebo. In postherpetic neuralgia, Dextromethorphan did not reduce pain (95% CI: 10% decrease in pain to 14% increase in pain, p = 0.72). Five of 31 patients who took Dextromethorphan dropped out due to sedation or ataxia during dose escalation, but the remaining patients all reached a reasonably well-tolerated maintenance dose. We conclude that Dextromethorphan or other low-affinity NMDA channel blockers may have promise in the treatment of painful diabetic neuropathy.
David R Jones - One of the best experts on this subject based on the ideXlab platform.
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Dextromethorphan to dextrorphan urinary metabolic ratio does not reflect Dextromethorphan oral clearance
Drug Metabolism and Disposition, 2005Co-Authors: S Borges, Mitchell A. Hamman, Stephen D. Hall, David R Jones, Lang Li, Christopher J GorskiAbstract:Dextromethorphan urinary metabolic ratio is widely used to determine the CYP2D6 phenotype, but its utility to reflect subtle differences in catalytic activity is unclear. We evaluated the capability of Dextromethorphan urinary metabolic ratio to predict Dextromethorphan oral clearance as a measure of CYP2D6 activity. Data from 10 healthy extensive metabolizers of CYP2D6 were given 30 mg of Dextromethorphan hydrobromide orally on two occasions. Blood and urine samples were collected for 72 h. Dextromethorphan and dextrorphan were determined in urine by high-performance liquid chromatography with fluorescence detection and in serum by liquid chromatography-mass spectrometry. The urinary metabolic ratio was very weakly correlated with Dextromethorphan oral clearance (r = 0.24; p = 0.04). In contrast, the Dextromethorphan oral clearance was highly correlated with the Dextromethorphan to dextrorphan area under the concentration-time curve ratio (r = 0.84; p = 0.005) and the 3-h (r = 0.60; p = 0.003), 4-h (r = 0.72, p
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characterization of Dextromethorphan n demethylation by human liver microsomes contribution of the cytochrome p450 3a cyp3a subfamily
Biochemical Pharmacology, 1994Co-Authors: Christopher J Gorski, Steven A Wrighton, Stephen D. Hall, David R JonesAbstract:In an effort to identify the human cytochromes P450 involved in the N-demethylation of Dextromethorphan, the kinetics of 3-methoxymorphinan formation were studied in microsomal enzyme systems. Under initial rate conditions, 3-methoxymorphinan formation demonstrated single enzyme Michaelis-Menten kinetics using microsomes obtained from three human livers (Km: 0.52–0.71 mM; Vmax: 375–812 pmol/mg protein/min). B-lymphoblastoid cells expressing CYP3A4 incubated with 0.4 mM Dextromethorphan catalyzed the formation of 3-methoxymorphinan at a rate of 22 pmol product/mg protein/min. Midazolam, a prototypic substrate for CYP3A4 and CYP3A5, competitively inhibited Dextromethorphan N-demethylation by two human liver microsomal samples with Ki values of 46 ± 10 and 63 ± 8 μM. At a Dextromethorphan concentration of 0.4 mM, gestodene (100 μM) inhibited 3-methoxymorphinan formation by approximately 50%. Immunoinhibition of dextro-methorphan N-demethylation using rabbit anti-CYP3A4 antibodies resulted in a 60% decrease in 3-methoxymorphinan formation at a Dextromethorphan concentration of 0.4 mM. Additional inhibition studies using furafylline, coumarin, sulfaphenazole, mephenytoin, quinidine, and diethyldithiocarbamic acid, which are selective inhibitors of CYP1A2, CYP2A6, CYP2C8/9, CYP2Cmp, CYP2D6, and CYP2E1, respectively, demonstrated no substantial inhibition of Dextromethorphan N-demethylation. Correlation analysis was performed using the rate of 3-methoxymorphinan formation at a concentration of 1mM Dextromethorphan and immunoquantified levels of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 and their associated characteristic catalytic activities. A significant correlation was observed between Dextromethorphan N-demethylase activity and midazolam 1'- and 4-hydroxylase activity (r2 = 0.77 and 0.69 respectively, N = 19, P < 0.01); the exclusion of those samples containing both CYP3A4 and CYP3A5 increased the correlation significantly (r2 = 0.87 and 0.91 respectively, N = 12, P < 0.01). In the absence of CYP3A5, a significant correlation was observed between 3-methoxymorphinan formation and the sample's erythromycin N-demethylase activity (r2= 0.94, N = 12, P < 0.01), testosterone 6 β-hydroxylase activity (r2 = 0.96, N = 7, P < 0.01) and relative immunoquantified levels of CYP3A4 (r2 = 0.96, N = 12, P < 0.01). Inclusion of those samples expressing CYP3A5 in addition to CYP3A4 reduced the magnitude of the observed correlation. No significant correlation between 3-methoxymorphinan formation and the sample's relative immunoquantified levels of or form-selective activity associated with CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19 (or CYP2Cmp), CYP2D6, and CYP2E1 was observed. In conclusion, Dextromethorphan N-demethylation appears to be catalyzed primarily by CYP3A4 and to a lesser extent by CYP3A5 in vitro in humans. Thus, the administration of Dextromethorphan to human volunteers may provide a means of simultaneously phenotyping the in vivo activity of CYP2D6 and CYP3A.
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characterization of Dextromethorphan n demethylation by human liver microsomes contribution of the cytochrome p450 3a cyp3a subfamily
Biochemical Pharmacology, 1994Co-Authors: Christopher J Gorski, Steven A Wrighton, Stephen D. Hall, David R JonesAbstract:In an effort to identify the human cytochromes P450 involved in the N-demethylation of Dextromethorphan, the kinetics of 3-methoxymorphinan formation were studied in microsomal enzyme systems. Under initial rate conditions, 3-methoxymorphinan formation demonstrated single enzyme Michaelis-Menten kinetics using microsomes obtained from three human livers (Km: 0.52-0.71 mM; Vmax: 375-812 pmol/mg protein/min). B-lymphoblastoid cells expressing CYP3A4 incubated with 0.4 mM Dextromethorphan catalyzed the formation of 3-methoxymorphinan at a rate of 22 pmol product/mg protein/min. Midazolam, a prototypic substrate for CYP3A4 and CYP3A5, competitively inhibited Dextromethorphan N-demethylation by two human liver microsomal samples with Ki values of 46 +/- 10 and 63 +/- 8 microM. At a Dextromethorphan concentration of 0.4 mM, gestodene (100 microM) inhibited 3-methoxymorphinan formation by approximately 50%. Immunoinhibition of Dextromethorphan N-demethylation using rabbit anti-CYP3A4 antibodies resulted in a 60% decrease in 3-methoxymorphinan formation at a Dextromethorphan concentration of 0.4 mM. Additional inhibition studies using furafylline, coumarin, sulfaphenazole, mephenytoin, quinidine, and diethyldithiocarbamic acid, which are selective inhibitors of CYP1A2, CYP2A6, CYP2C8/9, CYP2Cmp, CYP2D6, and CYP2E1, respectively, demonstrated no substantial inhibition of Dextromethorphan N-demethylation. Correlation analysis was performed using the rate of 3-methoxymorphinan formation at a concentration of 1 mM Dextromethorphan and immunoquantified levels of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 and their associated characteristic catalytic activities. A significant correlation was observed between Dextromethorphan N-demethylase activity and midazolam 1'- and 4-hydroxylase activity (r2 = 0.77 and 0.69 respectively, N = 19, P < 0.01); the exclusion of those samples containing both CYP3A4 and CYP3A5 increased the correlation significantly (r2 = 0.87 and 0.91 respectively, N = 12, P < 0.01). In the absence of CYP3A5, a significant correlation was observed between 3-methoxymorphinan formation and the sample's erythromycin N-demethylase activity (r2 = 0.94, N = 12, P < 0.01), testosterone 6 beta-hydroxylase activity (r2 = 0.96, N = 7, P < 0.01) and relative immunoquantified levels of CYP3A4 (r2 = 0.96, N = 12, P < 0.01). Inclusion of those samples expressing CYP3A5 in addition to CYP3A4 reduced the magnitude of the observed correlation. No significant correlation between 3-methoxymorphinan formation and the sample's relative immunoquantified levels of or form-selective activity associated with CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19 (or CYP2Cmp), CYP2D6, and CYP2E1 was observed. In conclusion, Dextromethorphan N-demethylation appears to be catalyzed primarily by CYP3A4 and to a lesser extent by CYP3A5 in vitro in humans.(ABSTRACT TRUNCATED AT 400 WORDS)
Jhijoung Wang - One of the best experts on this subject based on the ideXlab platform.
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systemic Dextromethorphan and dextrorphan are less toxic in rats than bupivacaine at equianesthetic doses
Canadian Journal of Anaesthesia-journal Canadien D Anesthesie, 2011Co-Authors: Yu Wen Chen, Jhijoung Wang, Yu-chung Chen, Ching Hsia HungAbstract:Purpose Dextrorphan, a major metabolite of Dextromethorphan, produces the duration of spinal and cutaneous anesthesia similar to bupivacaine. The purpose of this study was to test the central nervous system and cardiovascular toxicity of bupivacaine, Dextromethorphan, and dextrorphan.
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isobolographic analysis of epinephrine with bupivacaine Dextromethorphan 3 methoxymorphinan or dextrorphan on infiltrative anesthesia in rats dose response studies
Regional Anesthesia and Pain Medicine, 2008Co-Authors: Yu Wen Chen, Willy Chou, Jhijoung Wang, Ching Hsia HungAbstract:Background and Objectives The aims of this study were to establish the potencies of epinephrine, bupivacaine, Dextromethorphan, 3-methoxymorphinan, and dextrorphan and evaluate interactions of epinephrine with bupivacaine, Dextromethorphan, 3-methoxymorphinan, or dextrorphan as an infiltrative anesthetic. Bupivacaine, a common and long-acting local anesthetic, was used as control. Methods Dose-dependent responses of epinephrine, Dextromethorphan, 3-methoxymorphinan, and dextrorphan on cutaneous analgesia were compared with bupivacaine in rats. The interactions of drugs were evaluated via an isobolographic analysis. Results We found that epinephrine, bupivacaine, Dextromethorphan, 3-methoxymorphinan, and dextrorphan produced a dose-dependent local anesthetic effect as infiltrative cutaneous analgesia. Relative potencies were epinephrine > bupivacaine > Dextromethorphan > 3-methoxymorphinan > dextrorphan ( P Conclusions Epinephrine, Dextromethorphan, 3-methoxymorphinan, and dextrorphan are known to have local anesthetic effects as infiltrative cutaneous analgesia in rats. Epinephrine increased the potency of bupivacaine, but not Dextromethorphan, 3-methoxymorphinan, or dextrorphan as an infiltrative anesthetic. The cutaneous analgesic effects of adding epinephrine to Dextromethorphan, 3-methoxymorphinan, or dextrorphan, are similar to combinations of 2 local anesthetics.
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the spinal anaesthetic effect of Dextromethorphan dextrorphan and 3 methoxymorphinan
European Journal of Pharmacology, 2007Co-Authors: Yu Wen Chen, Yenchia Chen, Jhijoung WangAbstract:Abstract Dextromethorphan, an antitussive, has a complex pharmacologic profile and has not been well studied. Our aim was to evaluate whether Dextromethorphan and its metabolites, dextrorphan and 3-methoxymorphinan, have a spinal anaesthetic effect. Using a method of spinal blockade in rats, we evaluated the potencies and durations of the effects of Dextromethorphan and its metabolites on spinal blockades of motor function and nociception. Bupivacaine was the active control. We found that Dextromethorphan and its metabolites produced a dose-related spinal blockade of motor function and nociception. On an ED 50 basis, the ranks of potencies were bupivacaine > dextrorphan > 3-methoxymorphinan > Dextromethorphan ( p p
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Dextromethorphan or dextrorphan have a local anesthetic effect on infiltrative cutaneous analgesia in rats
Anesthesia & Analgesia, 2007Co-Authors: Yu Wen Chen, Janninn Tzeng, Jhijoung WangAbstract:BACKGROUND: Dextromethorphan blocks sodium channels, the site of action of local anesthetics. In this study we evaluated whether Dextromethorphan has a local anesthetic effect. METHODS: We administered Dextromethorphan and its active metabolite-dextrorphan, and lidocaine subcutaneously to rats and tested them for cutaneous anesthesia. Drug-drug interactions and systemic safety indices (LD 50 s/ED 50 s) were also evaluated. RESULTS: Dextromethorphan and dextrorphan had a local anesthetic effect after cutaneous infiltration. The ranking of potencies was Dextromethorphan > dextrorphan > lidocaine (P < 0.01 for each comparison). A combination of Dextromethorphan or dextrorphan with lidocaine produced an additive effect. Dextromethorphan and dextrorphan had 2.4- and 1.9-fold higher system safety indices than did lidocaine. CONCLUSION: Dextromethorphan and dextrorphan were more potent local anesthetics than lidocaine, but with higher systemic safety indices. Coadministration of Dextromethorphan or dextrorphan with lidocaine produced an additive effect.
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Dextromethorphan 3 methoxymorphinan and dextrorphan have local anaesthetic effect on sciatic nerve blockade in rats
European Journal of Pharmacology, 2006Co-Authors: Janninn Tzeng, Chiehhsien Tu, Yu Wen Chen, Jhijoung WangAbstract:AbstractDextromethorphan has been used as an antitussive for more than 40 years and is considered a drug with a good margin of safety. The aim of thestudy was to evaluate whether Dextromethorphan and its metabolites — 3-methoxymorphinan and dextrorphan— had local anaesthetic effects.Using a method of sciatic nerve blockade in rats, the potencies and durations of actions of Dextromethorphan and its metabolites on sciatic nerveblockades of motor function, proprioception, and nociception were evaluated. Lidocaine was used as control. We found that Dextromethorphanand its metabolites produced dose-related local anaesthetic effects on sciatic nerve blockades of motor function, proprioception, and nociception.The ranks of potencies were lidocaine>Dextromethorphan>3-methoxymorphinan>dextrorphan (P<0.01 for each comparison). Under an equi-potent basis, dextrorphan and 3-methoxymorphinan had durations of actions longer than that of lidocaine (P<0.05 for each comparison). Co-administration of Dextromethorphan or its metabolites with lidocaine produced an additive effect on sciatic nerve blockades. In conclusion,Dextromethorphan and its metabolites — 3-methoxymorphinan and dextrorphan— had a local anaesthetic effect on sciatic nerve blockades ofmotor function, proprioception and nociception with durations of actions longer than that of lidocaine. Co-administration of Dextromethorphan andits metabolites produced an additive effect on sciatic nerve blockades.© 2006 Elsevier B.V. All rights reserved.