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PubMed1995

N-methyl-D-aspartate (NMDA) receptors, mu and kappa opioid tolerance, and perspectives on new analgesic drug development.

This laboratory perspective reviews the pharmagologic approaches that have been used in preclinical animal models to demonstrate the ability of competitive (LY274614) and noncompetitive (MK801 and dextromethorphan) N-methyl-D-aspartate (NMDA) receptor antagonists to attenuate or reverse the development of morphine tolerance. We provide additional data to support previous observations that these NMDA antagonists modulate morphine (mu) opioid tolerance but do not affect U50488H (kappa 1) opioid tolerance. A strategy, which utilizes efficacy as an NMDA receptor antagonist and clinical safety, provides the basis for a discussion of the clinical potential of dextromethorphan, ketamine, and felbamate as modulators of opioid tolerance in pain patients or opioid addicts. The potential use of NMDA receptor antagonists and nitric oxide synthase (NOS) inhibitors in neuropathic pain is also discussed.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1994

CYP2D6-related oxidation polymorphism in Italy.

The distribution of the oxidation polymorphism related to cytochrome CYP2D6 (debrisoquine type) was determined in 246 healthy Italian volunteers. Phenotyping was based on HPLC determination of the dextrometorphan/dextrorphan concentration ratio (metabolic ratio) in urine samples collected over an 8 h interval following a single oral 30 mg dose of dextromethorphan hydrobromide. Urinary excretion of dextromethorphan showed a wide interindividual variability, ranging from < or = 0.04 to 3.9% and from 0.5 to 79.6% of the dose, respectively. Metabolic ratios ranged from < or = 0.001 to 6.6. Eleven of the 246 subjects showed a metabolic ratio greater than 0.30, indicating that 4.5% of the population could be ascribed to the poor metabolizer status. The frequency of the poor metabolizer phenotype in this population is within the range described for other Caucasian ethnic groups.

Cytochrome P-450 CYP2D6↗
PubMed2005

Effect of low-dose ritonavir (100 mg twice daily) on the activity of cytochrome P450 2D6 in healthy volunteers.

OBJECTIVE: In the treatment of human immunodeficiency virus infection, the protease inhibitor ritonavir is used in a low dose (100 mg twice daily) to inhibit cytochrome P450 (CYP) 3A4 and thereby increase plasma concentrations of coadministered protease inhibitors. When applied in a therapeutic dose (600 mg twice daily), ritonavir also inhibits CYP2D6. The effect of low-dose ritonavir on CYP2D6 is unknown and was investigated in this study. METHODS: This was a 1-arm, 2-period, fixed-order study in 13 healthy male volunteers who were extensive metabolizers of CYP2D6. The first period examined baseline CYP2D6 activity by evaluating the pharmacokinetics of a single dose of desipramine and by metabolic phenotyping with dextromethorphan. During the second period, participants took ritonavir, 100 mg twice daily, for 2 weeks, followed by repeat assessment of desipramine pharmacokinetics and the dextromethorphan metabolic phenotype in the presence of ritonavir. RESULTS: Low-dose ritonavir (100 mg twice daily) significantly increased the exposure to single-dose desipramine, as reflected in a geometric mean ratio (with ritonavir/without ritonavir) of 1.26 (95% confidence interval, 1.13-1.40) for the desipramine area under the concentration versus time curve from time 0 to infinity (P < .001). Coadministration of low-dose ritonavir did not significantly affect the dextromethorphan/dextrorphan urinary metabolic ratio and did not convert any extensive metabolizer to a poor metabolizer. CONCLUSIONS: Low-dose ritonavir (100 mg twice daily) exerts a modest inhibitory effect on the activity of CYP2D6 in extensive metabolizers, as assessed with desipramine as the index substrate. This effect was not apparent with the dextromethorphan/dextrorphan metabolic ratio as an indicator for CYP2D6 activity. It is expected that the effect of low-dose ritonavir on CYP2D6 will not require standard dose reductions for CYP2D6 substrates.

Adolescent↗
PubMed2006

Pseudobulbar affect in multiple sclerosis: toward the development of innovative therapeutic strategies.

Pseudobulbar affect (PBA), a condition involving involuntary and uncontrollable episodes of crying and/or laughing, occurs frequently in patients with a variety of neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury, dementia including Alzheimer's disease, and multiple sclerosis (MS). Although PBA results in considerable distress for patients and caretakers, it is underrecognized and undertreated. Agents used to treat psychiatric disorders--particularly tricyclic antidepressants and selective serotonin reuptake inhibitors--are useful in alleviating PBA, but act on diffuse neural networks rather than targeting those involved in emotional motor expression. As a result of their nonspecific activity, these agents are associated with a range of unwanted effects that preclude many patients from using them. Dextromethorphan, a common cough suppressant, specifically targets sigma(1) receptors concentrated in the brainstem and cerebellum, thus providing the possibility of targeting regions implicated in emotional expression. When administered in a fixed combination with quinidine, dextromethorphan is effective in treating PBA in patients with ALS, and preliminary results suggest that this therapy also is effective in treating MS-related PBA.

Adrenergic alpha-Antagonists↗
PubMed2005

Effect of St John's wort (Hypericum perforatum) on cytochrome P-450 activity in perfused rat liver.

St. John's wort (Hypericum perforatum) is a popular over-the-counter dietary supplement and a herbal antidepressant that has been implicated in drug interactions with substrates of several cytochrome P-450 (CYP) isozymes. The effects of the St. John's wort extract (100 mg/kg, i.p., once daily for 10 days) on metabolic activity of CYP450 were assessed in the system of isolated perfused rat liver. The substrates used in this study were tolbutamide (CYP2C6), dextromethorphan (CYP2D2) and midazolam (CYP3A2). Validated HPLC method was used to quantify all compounds of interest. St. John's wort administration affected CYP activity, causing a significant decline in AUC of dextromethorphan [F(4,31)=1511, p<0.001; PLSD, p<0.001] and AUC of midazolam [F(3,25)=221, p<0.001; PLSD, p=0.035] and a significant increase in AUC of tolbutamide [F(3,26)=200, p<0.001; PLSD, p<0.001]. St. John's wort administration resulted in a significant induction of CYP2D2 and CYP3A2, and in a significant inhibition of CYP2C6 metabolic activities.

Animals↗
PubMed2004

Modulation of morphine analgesia by site-specific N-methyl-D-aspartate receptor antagonists: dependence on sex, site of antagonism, morphine dose, and time.

Pharmacological blockade of N-methyl-D-aspartate (NMDA) receptors can modulate morphine analgesia in experimental animals and humans. However, this literature is highly inconsistent, with NMDA receptor antagonists variously shown to potentiate, attenuate or produce no effect on morphine analgesic magnitude. A number of factors influencing this modulation have been proposed, but no one has examined such factors simultaneously, and all existing studies in mice were conducted exclusively in male subjects. Thus, the influence of systemic administration of site-specific NMDA receptor antagonists-including dextromethorphan, dextrorphan, MK-801, LY235959, L-701,324, and Ro 25-6981-on morphine analgesia (15-45 mg/kg; 15, 30 and 60 min post-injection) was studied in male and female mice using the 49 degrees C tail-withdrawal test. We found that oral and intraperitoneal dextromethorphan, a low-affinity non-competitive antagonist, dose-dependently potentiated low-dose morphine analgesia but attenuated high-dose morphine analgesia. Dextrorphan and MK-801 were found to potentiate low- but not high-dose morphine analgesia. The competitive glutamate-site antagonist, LY235959, and glycine-site antagonist, L-701,324, potentiated morphine analgesia at all doses. In contrast, the polyamine (NR2B) site antagonist, Ro 25-6981, attenuated morphine analgesia at all doses. Strikingly, the non-competitive antagonists produced no modulation of morphine analgesia whatsoever in female mice, whereas no sex differences were observed using competitive or NR2B antagonists. These findings indicate that NMDA modulation of morphine analgesia is critically influenced by sex, site of antagonism, morphine dose and time after injection. Our data suggest that NMDA antagonism via competitive or glycine site antagonism might result in more reliable clinical effects on morphine analgesia in both sexes.

Animals↗
PubMed2005

MorphiDex (morphine sulfate/dextromethorphan hydrobromide combination) in the treatment of chronic pain: three multicenter, randomized, double-blind, controlled clinical trials fail to demonstrate enhanced opioid analgesia or reduction in tolerance.

While many pre-clinical and clinical studies have suggested that the addition of N-methyl-D-aspartate (NMDA) receptor antagonists, such as dextromethorphan (DM), to opioid analgesics, such as morphine (MS), may enhance the analgesic effects and prevent the tolerance that may result from chronic opioid administration, others have not. The potential for reduced doses, enhanced opioid analgesia, and decreased analgesic tolerance associated with the MS/DM combination were evaluated in a series of three large, randomized, double-blind, parallel group, phase 3, multicenter trials each of 3 months duration in patients with chronic, non-malignant, non-neuropathic pain. To evaluate these unique endpoints, novel study designs were employed. In Study A, patients received fixed doses of MS or MS/DM, based on the stable dose of MS/DM attained during a Run-in period; changes from baseline in average daily pain intensity were compared. In Studies B and C, patients self-titrated doses of MS or MS/DM, based on stable doses of MS or other opioids attained during Run-in periods, to maintain pain relief; percentage changes from baseline in MS (or MS-equivalent) doses were compared. No statistically significant differences between treatment groups in any primary or secondary efficacy variables were demonstrated in any trial. These results suggest that adding the NMDA antagonist, dextromethorphan, to opioids does not add any clinical benefit.

Adult↗
PubMed2005

NMDA antagonist modulation of morphine antinociception in female vs. male rats.

NMDA antagonists may be useful for their potential to increase or prolong opioid analgesia while attenuating the development of opioid tolerance and dependence. The purpose of this study was to determine whether there are sex differences in NMDA antagonist modulation of morphine antinociception. Adult female and male Sprague-Dawley rats were injected s.c. with saline or one dose of MK-801 (0.005, 0.01, 0.02, or 0.04 mg/kg), dextromethorphan (5, 10, or 20 mg/kg), or LY235959 (0.5, 1.0, or 2.0 mg/kg) in combination with saline or one dose of morphine (1.8, 3.2, or 5.6 mg/kg), and tested on the 50 degrees C hotplate and tail withdrawal assays 15-120 min post-injection. At the doses examined, only LY235959 produced any antinociception when administered alone. MK-801 attenuated morphine antinociception on both assays, but only at sporadic (inconsistent) dose-combinations. Dextromethorphan increased morphine antinociception on the hotplate but not tail withdrawal assay, at all three morphine doses in males, but only the higher morphine doses in females. In contrast, LY235959 modulated morphine antinociception on both assays; the lowest dose attenuated, and higher doses enhanced morphine antinociception, but the particular morphine doses and assay in which these effects occurred depended on the sex of the subject. Thus, all three NMDA antagonists modulated morphine antinociception in female and male rats, but the direction of this modulation depended on the particular antagonist examined, the nociceptive test, the dose of antagonist and of morphine, and time post-injection.

Analgesics, Opioid↗
PubMed2002

Substrate specificity for rat cytochrome P450 (CYP) isoforms: screening with cDNA-expressed systems of the rat.

In this study, we performed a screening of the specificities of rat cytochrome P450 (CYP) isoforms for metabolic reactions known as the specific probes of human CYP isoforms, using 13 rat CYP isoforms expressed in baculovirus-infected insect cells or B-lymphoblastoid cells. Among the metabolic reactions studied, diclofenac 4-hydroxylation (DFH), dextromethorphan O-demethylation (DMOD) and midazolam 4-hydroxylation were specifically catalyzed by CYP2C6, CYP2D2 and CYP3A1/3A2, respectively. These results suggest that diclofenac 4-hydroxylation, dextromethorphan O-demethylation and midazolam 4-hydroxylation are useful as catalytic markers of CYP2C6, CYP2D2 and CYP3A1/3A2, respectively. On the other hand, phenacetin O-deethylation and 7-ethoxyresorufin O-deethylation were catalyzed both by CYP1A2 and by CYP2C6. Benzyloxyresorufin O-dealkylation and pentoxyresorufin O-dealkylation were also catalyzed by CYP1A2 in addition to CYP2B1. Bufuralol 1'-hydroxylation was extensively catalyzed by CYP2D2 but also by CYP2C6 and CYP2C11. p-Nitrophenol 2-hydroxylation and chlorzoxazone 6-hydroxylation were extensively catalyzed by CYP2E1 but also by CYP1A2 and CYP3A1. Therefore, it is necessary to conduct further study to clarify whether these activities in rat liver microsomes are useful as probes of rat CYP isoforms. In contrast, coumarin 7-hydroxylation and S- and R-mephenytoin 4'-hydroxylation did not show selectivity toward any isoforms of rat CYP studied. Therefore, activities of coumarin 7-hydroxylation and S- and R-mephenytoin 4'-hydroxylation are not able to be used as catalytic probes of CYP isoforms in rat liver microsomes. These results may provide useful information regarding catalytic probes of rat CYPs for studies using rat liver microsomal samples.

Animals↗
PubMed2003

Effects of garlic (Allium sativum L.) supplementation on cytochrome P450 2D6 and 3A4 activity in healthy volunteers.

Garlic (Allium sativum L.) is a commonly used food and herbal supplement. The objective of this study was to assess in healthy volunteers (N = 14) the influence of a garlic extract on the activity of cytochrome P450 (CYP) 2D6 and 3A4. Probe substrates dextromethorphan (CYP2D6) and alprazolam (CYP3A4) were administered orally at baseline and again after treatment with garlic extract (3 x 600 mg twice daily) for 14 days. Urinary dextromethorphan/dextrorphan ratios and alprazolam plasma concentrations were determined by HPLC at baseline and after garlic extract treatment. The ratio of dextromethorphan to its metabolite was 0.044 +/- 0.48 at baseline and 0.052 +/- 0.095 after garlic supplementation. There were no significant differences between the baseline and garlic phases (P > or =.05). For alprazolam, there were no significant differences in pharmacokinetic parameters at baseline and after garlic extract treatment (all P values > or =.05; maximum concentration in plasma, 27.3 +/- 2.6 ng/mL versus 27.3 +/- 4.8 ng/mL; time to reach maximum concentration in plasma, 1.9 +/- 1.4 h versus 2.4 +/- 1.8 h; area under the time-versus-concentration curve, 537 +/- 94 h. ng. mL(-1) versus 548 +/- 159 h. ng. mL(-1); half-life of elimination, 13.7 +/- 4.4 h versus 14.5 +/- 4.3 h). Our results indicate that garlic extracts are unlikely to alter the disposition of coadministered medications primarily dependent on the CYP2D6 or CYP3A4 pathway of metabolism.

Adult↗
PubMed2003

Combined phenotypic assessment of cytochrome p450 1A2, 2C9, 2C19, 2D6, and 3A, N-acetyltransferase-2, and xanthine oxidase activities with the "Cooperstown 5+1 cocktail".

Previously, we have validated a 4-drug phenotyping cocktail, the "Cooperstown cocktail," using caffeine (cytochrome p450 [CYP] 1A2, N-acetyltransferase-2 [NAT2], and xanthine oxidase [XO]), dextromethorphan (CYP2D6), omeprazole (CYP2C19), and intravenous midazolam (hepatic CYP3A). Data suggest that warfarin can be used as a safe and accurate biomarker for CYP2C9, and if warfarin is administered with vitamin K, the pharmacodynamic effect is ablated. Twelve subjects received the Cooperstown cocktail, warfarin plus vitamin K, and both sets of biomarkers (Cooperstown 5+1 cocktail) in a randomized crossover fashion. On the basis of log-transformed data and a paired t test, no significant difference was seen for S-warfarin area under the serum concentration-time curve from time 0 to infinity (P =.09), omeprazole metabolic ratio (P =.374), caffeine metabolic ratio (P =.169 for CYP1A2 activity), midazolam plasma clearance (P =.573), or dextromethorphan metabolic ratio (P =.747) with the Cooperstown cocktail, warfarin plus vitamin K alone, or the Cooperstown 5+1 cocktail. During drug administration, the only side effect was mild and short-lived sedation after intravenous midazolam administration. Phenotypic measurements were in concordance with the subject's CYP2C9, CYP2C19, and CYP2D6 genotypes. The Cooperstown 5+1 cocktail may be used to simultaneously assess the activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A, NAT2, and XO.

Acetyltransferases↗
PubMed1997

Influence of stiripentol on cytochrome P450-mediated metabolic pathways in humans: in vitro and in vivo comparison and calculation of in vivo inhibition constants.

OBJECTIVE: The spectrum of cytochrome P450 inhibition of stiripentol, a new anticonvulsant, was characterized in vitro and in vivo. METHODS: Stiripentol was incubated in vitro with (R)-warfarin, coumarin, (S)-warfarin, (S)-mephenytoin, bufuralol, p-nitrophenol, and carbamazepine as probes for CYPs 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4, respectively. Caffeine demethylation and the 6 beta-hydroxycortisol/cortisol ratio were monitored in vivo before and after 14 days of treatment with stiripentol as measures of CYP1A2 and CYP3A4 activity, and dextromethorphan O- and N-demethylation were used to measure CYP2D6 and CYP3A4 activity, respectively. In vivo inhibition constants for CYP3A4 were calculated with use of data that previously documented the interaction between stripentol and carbamazepine. RESULTS: In vitro, stiripentol inhibited CYPs 1A2, 2C9, 2C19, 2D6, and 3A4, with inhibition constant values at or slightly higher than therapeutic (total) concentrations of stiripentol, but it did not inhibit CYPs 2A6 and 2E1 even at tenfold therapeutic concentrations. In vivo inhibition of caffeine demethylation and dextromethorphan N-demethylation were consistent with inhibition of CYP1A2 and CYP3A4, respectively. The 6 beta-hydroxycortisol/cortisol ratio did not provide a reliable index of CYP3A4 inhibition. Inhibition of CYP2D6-mediated O-demethylation was not observed in vivo. With use of carbamazepine, in vivo inhibition constants for CYP3A4 ranged between 12 and 35 mumol/L, whereas the corresponding in vitro value was 80 mumol/L. CONCLUSIONS: Stiripentol appears to inhibit several CYP450 enzymes in vitro and in vivo. In vivo inhibition constants show that stiripentol inhibition of CYP3A4 is linearly related to plasma concentration in patients with epilepsy.

Adult↗
PubMed1999

Effects of dopaminergic agents and of an NMDA receptor antagonist on motor coordination in Lurcher mutant mice.

Lurcher mutant mice, characterized by an ataxic gait and olivocerebellar degeneration, were evaluated for motor coordination in the coat-hanger test after peripheral injections of two doses of dextromethorphan, a noncompetitive N-methyl-D-aspartate receptor antagonist, L-dopa/carbidopa, and SKF 77434, a dopamine D1 receptor agonist. There was an improvement in the distance traveled on the suspended horizontal string after 25 and 50 mg/kg of dextromethorphan and 37.5 mg/kg of L-dopa/carbidopa, but not after SKF 77434. None of the drugs reduced movement times or increased latencies before falling. These results indicate that NMDA receptor antagonism or stimulation of some dopaminergic mechanisms partially improve genetically determined cerebellar ataxia in mice.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1995

Lack of neuroprotective effect of sigma receptor ligands in the neurotoxicity of p-chloroamphetamine in rat brain.

We studied the mechanism of antagonism of p-chloroamphetamine-induced neurotoxicity by dextromethorphan. The pretreatment with potent and selective sigma receptor ligands, 4-phenyl-4-(1-phenylbutyl)piperidine (4-PPBP) and N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100), did not alter the reduction of 5-hydroxytryptamine and 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the cerebral cortex by repeated administration of p-chloroamphetamine. These results suggest that sigma receptors might not play a significant role in the antagonism of p-chloroamphetamine-induced neurotoxicity by dextromethorphan.

Animals↗
PubMed2000

Evaluation of a novel high-throughput assay for cytochrome P450 2D6 using 7-methoxy-4-(aminomethyl)-coumarin.

We recently reported on the design, synthesis and characterisation of a novel and selective substrate of human cytochrome P450 2D6 (CYP2D6), 7-methoxy-4-(aminomethyl)-coumarin (MAMC). Here, we describe a high-throughput microplate reader assay, which makes use of MAMC as a fluorescent probe for determining the inhibition and activity of CYP2D6 in heterologously expressed systems and human liver microsomes. The high-throughput screening (HTS) assay can be used both in an end-point and real-time configuration, and is easy to use, rapid and sensitive. In addition, end-point measurements by means of flow injection analysis have also successfully been performed. The HTS-assay was validated by performing inhibition experiments for several low- and high-affinity ligands (n=6) of CYP2D6, and comparing the findings to those obtained with the standard O-demethylation assay of dextromethorphan. The results indicate that all compounds tested display competitive inhibition in both the MAMC and dextromethorphan assay, and the K(i) values reveal a very good correlation (R(2)=0.984) between the two assays. To further demonstrate the usefulness of the HTS-assay, IC(50) values of a series of five N-substituted analogs of 3, 4-methylenedioxyamphetamine for CYP2D6 have been determined. The results obtained demonstrate that the current HTS-assay represents a significant improvement over previous assays, with a higher turnover of MAMC and a higher selectivity for CYP2D6.

Calibration↗
PubMed2001

Increasing bioanalytical throughput using pcSFC-MS/MS: 10 minutes per 96-well plate.

The utility of packed-column supercritical, subcritical, and enhanced fluidity liquid chromatographies (pcSFC) for high-throughput applications has increased during the past few years. In contrast to traditional reversed-phase liquid chromatography, the addition of a volatile component to the mobile phase, such as CO2, produces a lower mobile-phase viscosity. This allows the use of higher flow rates which can translate into faster analysis times. In addition, the resulting mobile phase is considerably more volatile than the aqueous-based mobile phases that are typically used with LC-MS, allowing the entire effluent to be directed into the MS interface. High-throughput bioanalytical quantitation using pcSFC-MS/MS for pharmacokinetics applications is demonstrated in this report using dextromethorphan as a model compound. Plasma samples were prepared by automated liquid/liquid extraction in the 96-well format prior to pcSFC-MS/MS analysis. Three days of validation data are provided along with study sample data from a patient dosed with commercially available Vicks 44. Using pcSFC and MS/MS, dextromethorphan was quantified in 96-well plates at a rate of approximately 10 min/plate with average intraday accuracy of 9% or better. Daily relative standard deviations (RSDs) were less than 10% for the 2.21 and 14.8 ng/mL quality control (QC) samples, while the RSDs were less than 15% at the 0.554 ng/mL QC level.

Antitussive Agents↗
PubMed1992

Synthesis and evaluation of 3-substituted 17-methylmorphinan analogs as potential anticonvulsant agents.

Dextromethorphan (1,(+)-3-methoxy-17-methylmorphinan) demonstrates anticonvulsant activity in a variety of in vitro and in vivo models of convulsive action. It is well known that 1 is metabolized to its phenolic derivative dextrorphan (2) and this metabolite is also a potent anticonvulsant. A series of (+)-3-substituted-17-methylmorphinans, which are structurally similar to 1 but are either not expected to be metabolized to 2 or might do so at a reduced rate, as compared to 1, were prepared. Three analogs, 5 ((+)-3-amino-17-methylmorphinan), 14 ((+)-3-ethoxy-17-methylmorphinan), and 15 ((+)-3-(2-propoxy)-17-methylmorphinan) were found to possess potent anticonvulsant activity with full efficacy (ED50 25, 5.6, and 3.9 mg/kg, sc, respectively) in the rat supramaximal electroshock (MES) test. Binding potencies of these compounds to receptor sites labeled with [3H]dextromethorphan ([3H]1), in rat brain and guinea pig brain subcellular fractions, and [3H]thienylcyclohexylpiperidine (TCP) and [3H]glycine in rat brain, were determined. Most of the analogs displaced [3H]1 from its binding sites, with compounds 14 (IC50 0.42 microM) and 15 (IC50 0.88 microM) having equivalent potencies to 1 (IC50 0.59 microM), in rat brain, and no appreciable activity at the [3H]TCP or [3H]glycine-labeled sites. Compound 5 did not bind with appreciable activity to the [3H]1 site, in rat brain, but did bind to the [3H]TCP site with lower potency than the parent 1 (IC50 7.8 and 2.0 microM, respectively). The mechanism of anticonvulsant action of these agents is not clear although it appears that interaction at the [3H]1 sites may be involved.

Animals↗
PubMed1992

Ethylmorphine O-deethylation cosegregates with the debrisoquin genetic metabolic polymorphism.

The single oral dose kinetics of ethylmorphine and its fractional metabolic clearance by O-dealkylation and N-dealkylation was investigated in five extensive and four poor metabolizers of dextromethorphan. In addition, the urinary metabolic ratios for these pathways (MRO and MRN, respectively) were investigated in a larger group of 27 extensive metabolizers and six poor metabolizers. The mean values for the fractional metabolic clearance by O-dealkylation and the MRO differed significantly between the poor metabolizers and extensive metabolizers without overlap between the values of either of these parameters in the two groups of subjects. In contrast, the corresponding parameters for the N-demethylation did not differ between poor metabolizers and extensive metabolizers. The area under the plasma concentration versus time curve was significantly higher (about three times higher) in the poor metabolizers compared with the extensive metabolizers (p = 0.004). Our data suggest that ethylmorphine is O-deethylated by the cytochrome P4502D6 isozyme inasmuch as both the fractional metabolic clearance by O-dealkylation and the MRO were found to cosegregate with the phenotype for the O-demethylation of dextromethorphan in our group of subjects.

Adult↗