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PubMed1996

The effects of N-methyl-D-aspartate agonists and antagonists on isolated bovine cerebral arteries.

This pharmacologic study examines the direct cerebrovascular effects of N-methyl-D-aspartate (NMDA) receptor agonists and antagonists to determine whether large cerebral arteries have NMDA receptors. Bovine middle cerebral arteries were cut into rings to measure isometric tension development in vitro. Two competitive agonists, L-glutamate and NMDA, each had negligible effects on ring tension in the absence of exogenous vasoconstrictors. L-glutamate (in high concentrations) produced direct relaxation of potassium (K+)-constricted arteries, but the relaxation was not selective for L-glutamate, D-glutamate, or mannitol. Relaxation with L-glutamate was abolished when it was isosmotically substituted in the K(+)-rich medium. NMDA (in the absence or presence of glycine) and two competitive antagonists, 2-amino-5-phosphopentanoic acid (AP5) and (+/-)-3-(s-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), each had little effect on the tone of arteries preconstricted with potassium or the stable thromboxane A2 analog U-46,619. Three noncompetitive antagonists (S(+)-ketamine, dizocilpine, and dextrorphan) and their steroeisomers (R(-)-ketamine, (-)MK-801, and levorphanol) each produced dose-dependent relaxation of K(+)- or U-46,619-constricted arteries; relaxation was not selective for the (+) or (-) stereoisomers. These results suggest that large cerebral arteries lack NMDA receptors mediating constriction or relaxation. All noncompetitive antagonists dilated cerebral arteries, but by mechanisms that were not stereospecific.

Animals↗
PubMed1991

Opioids potentiate contractile response of rabbit myocardium to the beta adrenergic agonist isoproterenol.

Opioid agonists and antagonists have both been reported to augment myocardial contractile force in vitro. We reported that the strong opioid agonists morphine and levorphanol, the weak agonist dextrorphan (an optical isomer of levorphanol), and the opioid antagonist naloxone all potentiate the stimulatory effects of the beta-adrenergic agonist isoproterenol on isometric tension generated by isolated rabbit right ventricular myocardium. The EC50 of isoproterenol was found to be shifted leftward 2.7-, 5.4-, 5.3-, and 3.4-fold respectively (p less than 0.05 when compared with controls), when the opioids were added at a final concentration of 1 x 10(5) M. Lower concentrations of opioid or antagonist did not potentiate the effects of isoproterenol. The rank order potency for potentiation thus differs markedly from that of opioid analgesia. The observed potentiation is therefore not agonist specific and not stereospecific. Furthermore, the drugs alone at a range of concentration from 10(-8) to 10(-5) M had no effect on isometric tension generated. We conclude that opioid agonists and antagonists potentiate the response of ventricular myocardium to the effects of beta-adrenergic stimulation by a novel mechanism unrelated to the binding of these drugs to opioid receptors. The paradoxical augmentation of myocardial contractility by either class of agent under a variety of clinical and experimental conditions is thus explained by these findings. Either agent may interact with myocardial tissue to cause increased sensitivity to stimulation by circulating catecholamines.

Adrenergic beta-Agonists↗
PubMed1988

Simplified phenotyping with dextromethorphan by thin-layer chromatography: application to clinical laboratory screening for deficiencies in oxidative drug metabolism.

Identifying individuals with a deficient capacity for oxidative drug metabolism is of increasing clinical importance. Dextromethorphan (DM) is gaining wide acceptance as a probe drug to characterize individual expression of a specific cytochrome P-450 isozyme. The thin-layer chromatography (TLC) technique described in the present study is a rapid and inexpensive alternative to the methods currently available for assessing the urinary metabolic profile of DM. Sixty-five healthy volunteers participated in the study by ingesting 213 mmol DM and collecting all urine for the ensuing 8 h. Urine samples were analyzed by TLC and high-performance liquid chromatography (HPLC) after treatment with beta-glucuronidase. Based on the relative color intensities of DM and its O-demethylated metabolite, dextrorphan, the TLC analysis provided an accurate phenotype assessment. A greater intensity of the parent drug relative to the metabolite indicates a poor metabolizer phenotype whereas a reversed relative intensity indicates the extensive metabolizer phenotype. The phenotype assignments made by TLC were verified by comparison with the quantitative results (based on metabolic ratios) obtained from HPLC analysis. Complete agreement was found between the two methods. The routine implementation of phenotype determination into clinical protocols can be realized with this facile TLC technique.

Adolescent↗
PubMed1990

Simultaneous determination of dextromethorphan and three metabolites in plasma and urine using high-performance liquid chromatography with application to their disposition in man.

A simple, sensitive, and reproducible high-performance liquid chromatrography assay is described for the simultaneous determination of dextromethophan, dextrorphan, 3-hydroxymorphinan, and 3-methoxymorphinan in plasma and urine. A conventional solvent-solvent extraction procedure was used for the isolation of the analytes from plasma and urine samples. The compounds were separated on a cyano column (150 x 4.6 mm, 5-micron particle size) using a mobile phase of acetonitrile/triethylamine/distilled water (17:0.06:82.94, vol/vol), pH 3.0, and then were measured by fluorescence detection. Calibration curves in the range 2-200 ng/ml for plasma and 0.05-10 micrograms/ml for urine were linear and passed through the origin. The precision and accuracy were greater than 90% and the lowest detectable concentrations were 0.5 ng/ml for 3-hydroxymorphinan and 3-methoxymorphinan and 1 ng/ml for dextromethorphan and dextrophan in plasma. The utility of this method is demonstrated in a preliminary study of dextromethorphan metabolism and pharmacokinetics in man.

Chromatography, High Pressure Liquid↗
PubMed1995

Dextromethorphan polymorphic hepatic oxidation (CYP2D6) in healthy black American adult subjects.

The objective of this study was to assign metabolizer phenotype to 107 healthy adult black Americans using dextromethorphan as the substrate probe. Eligible subjects were unrelated, healthy, nonsmoking, aged 18-50 years, and taking no medications. Fifteen milliliters of dextromethorphan syrup (85 mumol, 30 mg) was administered orally at bedtime, and 8-h overnight urine was collected. Dextromethorphan and dextrorphan urinary areas and molar ratios were determined using high-performance liquid chromatography with fluorescence detection. A molar metabolic ratio of < 0.3 was used to segregate poor metabolizers (PM) from extensive metabolizers (EM). Data were obtained in 99 subjects: 68 women, 31 men. (Five were lost to follow-up, three did not take the probe drug.) Six (6.1%) were PM (five women, one man), and 93 were EM. The prevalence of PM was 6.1% (95% confidence interval, 2.3-12.7%) in our sample. This compares to 5 to 10% reported in white unrelated subjects and 1.9% in 106 black children (64 healthy and 42 with cancer), and 0-8.6% in black African populations. The clinical implications of these findings warrant further investigation.

Administration, Oral↗
PubMed2004

Analgesic effect of dextromethorphan in neuropathic pain.

BACKGROUND: Dextromethorphan, a clinically available N-methyl-D-aspartic acid (NMDA) receptor antagonist, has an analgesic effect in patients with diabetic neuropathy. The aim of this study was to evaluate the analgesic and adverse effects of a single high dose of dextromethorphan on spontaneous pain in patients suffering long-term neuropathic pain of traumatic origin. METHODS: Fifteen patients with post-traumatic neuropathic pain participated in this placebo-controlled, double-blind, randomized crossover study. On two separate occasions, the participants received 270 mg of dextromethorphan hydrobromide or placebo. Pain intensity, adverse effects and serum concentrations of dextromethorphan and metabolites were registered. RESULTS: Dextromethorphan had a statistically significant analgesic effect compared with placebo, but the effect varied markedly among the patients. Light-headedness was the most important adverse effect reported. Extensive metabolizers of dextromethorphan had an apparently better analgesic effect than poor metabolizers. CONCLUSION: This report indicates that a single high dose of dextromethorphan has an analgesic effect in patients with neuropathic pain of traumatic origin. The main metabolite dextrorphan seems to be important for the analgesic effect. At the relatively high dose studied, the clinical usefulness of dextromethorphan is limited to that portion of the patient population experiencing analgesia without an unacceptable level of adverse effects.

Adult↗
PubMed1989

Effect of liver disease on dextromethorphan oxidation capacity and phenotype: a study in 107 patients.

1. The O-demethylation of dextromethorphan to dextrorphan exhibits a genetically-controlled polymorphism, co-segregating with that of debrisoquine hydroxylation. Dextromethorphan has been proposed as a test compound to assess drug oxidation polymorphism. 2. We studied the effects of liver disease of varying severity on dextromethorphan oxidation capacity. Phenotyping was performed using the urinary dextromethorphan/dextrorphan metabolic ratio after oral administration of 40 mg dextromethorphan hydrobromide in 56 patients with cirrhosis and in 51 patients with moderately severe liver disease. 3. Dextromethorphan oxidation capacity was impaired in cirrhotic patients and, to lesser extent, in non cirrhotic patients, as compared with 103 control subjects. 4. The impairment in dextromethorphan oxidation induced by liver disease, was however, much less than that caused by the genetic deficiency. As a result, the prevalence of the poor metabolizer phenotype remained in the same range in patients with cirrhosis (1.8%) and with moderately severe disease (2.0%) as in controls (3.9%). 5. This observation shows that, although liver disease causes some impairment of dextromethorphan O-demethylation, this impairment is not sufficient to modify the assignment of phenotypes.

Adult↗
PubMed1994

The role of CYP2D6 in primary and secondary oxidative metabolism of dextromethorphan: in vitro studies using human liver microsomes.

1. The enzyme kinetics of dextromethorphan O-demethylation in liver microsomes from three extensive metabolisers (EM) with respect to CYP2D6 indicated high (Km1 2.2-9.4 microM) and low (Km2 55.5-307.3 microM) affinity sites whereas microsomes from two poor metabolisers (PM) indicated a single site (Km 560 and 157 microM). Similar differences were shown for 3-methoxymorphinan O-demethylation to 3-hydroxymorphinan (Km 6.9-9.6 microM in EM subjects; Km 307 and 213 microM in PM subjects). 2. Dextromethorphan O-demethylation was inhibited competitively by quinidine (Ki 0.1 microM), rac-perhexiline (Ki 0.4 microM), dextropropoxyphene (Ki 6 microM), rac-methadone (Ki 8 microM), and 3-methoxymorphinan (Ki 15 microM). These compounds were also potent inhibitors of 3-methoxymorphinan O-demethylation with IC50 values ranging from 0.02-12 microM. Anti-LKM1 serum inhibited both dextromethorphan and 3-methoxymorphinan O-demethylations in a titre-dependent manner. 3. The Michaelis-Menten constant for dextromethorphan N-demethylation to 3-methoxymorphinan (Km 632-977 microM) and dextrorphan N-demethylation to 3-hydroxymorphinan (Km 1571-4286 microM) did not differ between EM and PM microsomes. These N-demethylation reactions were not inhibited by quinidine and rac-methadone or LKM1 antibodies. 4. Dextromethorphan and 3-methoxymorphinan are metabolised by the same P450 isoform, CYP2D6, whereas the N-demethylation reactions are not carried out by CYP2D6.

Autoantibodies↗
PubMed1984

Antinociception from a stereospecific action of morphine microinjected into the brainstem: a local or distant site of action?

Morphine (1 microgram) was microinjected into rats in the midline medullary nucleus raphe magnus (NRM); 1 mm lateral into nucleus reticularis paragigantocellularis (NRPG); 2 mm lateral into the VIIth nerve nucleus and 3 mm lateral into the Vth nerve nucleus. The time course of changes in the sensitivity to noxious heat was followed by the tail flick test. Significant and prolonged antinociception was seen following microinjection into NRPG. At sites 1 mm from NRPG very weak effects were seen and at 2 mm from NRPG no antinociception occurred. It is concluded that 1 microgram of morphine microinjected into the brainstem is unlikely to cause antinociception by entering the circulation and having effects at remote sites. The distance diffused by morphine to cause significant antinociception after microinjection of 1 microgram is less than 1 mm. Levorphanol (1 microgram) had very similar effects to morphine but dextrorphan and saline were ineffective. It is concluded that although the concentrations achieved following microinjections may be high, they are not excessive as the effects show stereospecificity. The concentrations of endogenous substances released into the synaptic cleft may also be high.

Analgesics↗
PubMed1994

Dextromethorphan: cellular effects reducing neuronal hyperactivity.

Dextromethorphan is a dextrorotary morphinan without affinity for opioid receptors, commonly used as an antitussive medication. During the past 5 years, interest in the compound and its demethylated derivative, dextrorphan, has been revived because additional neuroprotective and antiepileptic properties were found in in vitro studies, animal experiments, and a few clinical cases. Both morphinans are able to inhibit N-methyl-D-aspartate (NMDA) receptor channels and voltage-operated calcium and sodium channels with different potencies. The inhibition of the NMDA receptor is believed to be the predominant mechanism of action responsible for the anticonvulsant and neuroprotective properties of the compounds.

Animals↗
PubMed2006

Selective effects of nitric oxide on the disposition of chlorzoxazone and dextromethorphan in isolated perfused rat livers.

The rapid and direct effects of nitric oxide (NO) donors sodium nitroprusside (SNP) and isosorbide dinitrate (ISDN) on the hepatic and biliary disposition of chlorzoxazone (CZX), a marker of CYP2E1, and dextromethorphan (DEM), a marker of CYP2D1, were studied in a single-pass isolated perfused rat liver model. Livers (n = 30) were perfused with constant concentrations of NO donors (0-120 min) in addition to infusion of CZX or DEM (60-120 min), and periodical outlet and bile samples were collected. Both ISDN and SNP significantly reduced (30 and 60%, respectively) the hepatic extraction ratio of CZX and decreased (50 and 70%, respectively) the recovery of the CYP2E1-mediated metabolite, 6-hydroxychlorzoxazone, in the outlet perfusate and bile. As for DEM, both NO donors increased (up to 3.5-fold) the recovery of the CYP2D1-mediated metabolite dextrorphan (DOR) in the outlet perfusate. However, this was associated with a simultaneous decrease (50-75%) in the excretion of the metabolite into the bile, thus resulting in no change in the overall recovery of DOR as a result of NO donor treatment. The decrease in the biliary excretion of DOR was caused by NO-induced simultaneous reductions in both the conjugation of DOR and biliary clearance of DOR conjugate. Additionally, both SNP and ISDN significantly reduced the metabolism of DEM to 3-hydroxymorphinan, which is mostly regulated by CYP3A2. These studies in an intact liver model confirm the selectivity of the inhibitory effects of NO donors on cytochrome P450 enzymes, which was recently reported in microsomal studies, and expand these inhibitory effects to conjugation pathways.

Alcohol Oxidoreductases↗
PubMed1975

Solubilization of a stereospecific opiate-macromolecular complex from rat brain.

A [3H]etorphine-macromolecular complex has been solubilized from rat brain synaptosomal fraction by extraction with the nonionic detergent Brij 36T. Stereospecificity of binding to this solubilized complex was demonstrated by the finding that radioactivity in the complex was virtually eliminated when binding had occurred in the presence of excess levorphanol, an active narcotic analgesic, while it was unaffected by its inactive enantiomorph dextrorphan. Bound radioactivity was dissociated by proteolytic enzymes, sulfhydryl reagents, and heat, suggesting the presence of protein. The bound solubilized macromolecular moiety may be the opiate receptor.

Animals↗
PubMed1989

The role of excitatory amino acids and NMDA receptors in traumatic brain injury.

Brain injury induced by fluid percussion in rats caused a marked elevation in extracellular glutamate and aspartate adjacent to the trauma site. This increase in excitatory amino acids was related to the severity of the injury and was associated with a reduction in cellular bioenergetic state and intracellular free magnesium. Treatment with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dextrophan or the competitive antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid limited the resultant neurological dysfunction; dextrorphan treatment also improved the bioenergetic state after trauma and increased the intracellular free magnesium. Thus, excitatory amino acids contribute to delayed tissue damage after brain trauma; NMDA antagonists may be of benefit in treating acute head injury.

Animals↗
PubMed1998

Effects of NMDA receptor antagonists on D1 dopamine receptor-mediated changes in striatal immediate early gene expression: evidence for involvement of pharmacologically distinct NMDA receptors?

Dopamine D1 receptor regulation of striatal gene expression is dependent on N-methyl-D-aspartate (NMDA) receptors. To determine whether pharmacologically distinct NMDA receptors are differentially involved, we examined the effects of different NMDA receptor antagonists on D1-induced immediate early gene expression. Systemic administration of the channel blocking antagonists MK-801 and dextrorphan and the competitive antagonist CGS 19755 blocked gene expression induced by the D1 agonist SKF 82958. The NMDA polyamine site antagonist ifenprodil, however, potentiated the effect of SKF 82958. Since ifenprodil is selective for receptors containing the NR2B subunit, the data suggest that subtypes of NMDA receptors may be differentially involved in regulating striatal function.

Animals↗
PubMed1978

Effects of opiates on cAMP in homogenates and slices of rat striata.

In slices of rat striata, incubated in a depolarizing medium (53 mM K+), morphine decreased by concentration of cAMP even in concentrations as low as 0.5 micron. This effect was inhibited by naloxone. Levorphanol, but not dextrorphan, induced a similar effect as morphine. In tissue, homogenized in a hypotonic medium, morphine (5-50 micron) also slightly decreased the concentration of cAMP, which was antagonized by naloxone. Neigher slices nor homogenates of morphine-withdrawn rats showed any alteration in the concentration of cAMP.

Animals↗
PubMed2001

Effect of venlafaxine versus fluoxetine on metabolism of dextromethorphan, a CYP2D6 probe.

Two antidepressants, venlafaxine and fluoxetine, were evaluated in vivo for their effect on cytochrome P450 2D6 (CYP2D6) activity, measured by the ratio of dextromethorphan, a sensitive CYP2D6 marker, to its metabolite dextrorphan (i.e., DM:DT) excreted in urine after DM coadministration. Twenty-eight healthy extensive metabolizers of CYP2D6 received either venlafaxine (37.5 mg bid for 7 days, then 75 mg bid until Day 28) or fluoxetine (20 mg daily for 28 days); 26 completed the study. Plasma concentrations of both drugs and their active metabolites were determined. DM:DTs were evaluated at baseline (Day 0), on Days 7 and 28 of dosing, and 2 weeks after drug discontinuation (Day 42). Steady-state drug and metabolite levels were achieved in both groups by Day 28. Mean DM:DTs for venlafaxine and fluoxetine differed statistically significantly (p < 0.001) on Days 7, 28, and 42. Comparisons of DM:DT as a percentage of baseline values showed that DM:DT increased 1.2-fold for venlafaxine and 9.1-fold for fluoxetine on Day 7 (p < 0.001) and increased 2.1-fold for venlafaxine and 17.1-fold for fluoxetine on Day 28 (p < 0.001). Inhibition of CYP2D6 metabolism persisted for 2 weeks after discontinuation of fluoxetine, unlike the case with venlafaxine. These in vivo results confirm in vitro data demonstrating significantly weaker inhibition of CYP2D6 with venlafaxine than with fluoxetine. This suggests that clinically significant interactions involving CYP2D6 inhibition could occur between fluoxetine and drugs metabolized by CYP2D6 but may be less likely to occur with venlafaxine.

Administration, Oral↗
PubMed2006

The impact of experimental design on assessing mechanism-based inactivation of CYP2D6 by MDMA (Ecstasy).

MDMA (3-4-methylenedioxymethamphetamine, commonly known as Ecstasy) is a potent mechanism-based inhibitor (MBI) of cytochrome P450 2D6 (CYP2D6), causing quasi-irreversible inhibition of the enzyme in vitro. An evaluation of the in vivo implications of this phenomenon depends on the accuracy of the estimates of the parameters that define the inhibition in vitro, namely k(inact) (the maximal inhibition rate) and KI (the inactivation constant). These values are determined in two steps, pre-incubation of the enzyme with the inhibitor (enzyme inactivation), followed by dilution and further incubation to measure residual enzyme activity with a probe substrate. The aim of this study was to assess the impact of different dilutions and probe substrate concentrations on the estimates of k(inact) and KI using recombinantly expressed CYP2D6. Enzyme activity was measured by the conversion of dextromethorphan (DEX) to dextrorphan (DOR). Dilution factors of 1.25, 2, 5, 10, 25 and 50 (DEX at 30 microM) gave mean (+/-SE) values of k(inact) (min-1) of 0.20+/-0.06, 0.21+/-0.05, 0.31+/-0.06, 0.37+/-0.11, 0.51+/-0.10 and 0.58+/-0.08, respectively, and KI (microM) values (after correction for non-specific microsomal binding) of 2.22+/-1.90, 2.80+/-1.34, 5.78+/-2.07, 6.36+/-2.93, 3.99+/-1.57 and 4.86+/-1.37, respectively. Accordingly, high (e.g. 50 fold) and low (e.g. 1.25 fold) dilutions were associated with statistically significant differences in kinetic values (p <0.05). Varying DEX concentration (10-100 microM) was not associated with significant changes in k(inact) and KI values when a five-fold dilution was used (with the exception of a lower KI at 10 microM DEX). High dilution was also shown to reduce non-specific microsomal binding of MDMA. The changes in the two kinetic parameters were dependent on the experimental procedure and shown to be unlikely to have a material influence on the maximum inhibition of CYP2D6 expected in vivo after typical recreational doses of MDMA (50-100 mg), since the potency of inhibition was high. The different values of the kinetic parameters were predicted to have a marginal influence on the time for recovery of enzyme activity following re-synthesis of CYP2D6.

Biotransformation↗
PubMed1994

Dextromethorphan test for evaluation of congenital predisposition to lung cancer.

We report the results of an investigation conducted in 992 healthy control subjects (854 adults and 138 adolescents) and in 116 subjects with lung cancer (LC) for the purpose of detecting those individuals with a possible genetic predisposition to lung cancer. The test consists of the oral administration of 64 mumol of dextromethorphan (DMP) with collection of urine samples over the following 8-h period and urine assay of the drug (DMP) and its main metabolite, dextrorphan (DOP). The ratio of the urinary concentrations of DMP to those of DOP is called the metabolic ratio (DMP/DOP) and is inversely proportional to the DMP demethylation rate. The pattern of the metabolic ratio (Log10 DMP/DOP) allowed, using a maximum likelihood approach, the identification of three subpopulations in the 854 control subjects (adults): (1) probable homozygous extensive metabolizers with Log10 DMP/DOP < -1.74 (73.1 percent); (2) probable heterozygous intermediate metabolizers with Log10 DMP/DOP in the -1.74 to -0.40 range (22.3 percent); and (3) probable homozygous poor metabolizers with Log10 DMP/DOP > -0.4 (4.6 percent). Most of the patients with LC (89 percent) were probable homozygous extensive metabolizers. As the latter have a cancer risk that is 2.54-fold greater than that of intermediate metabolizers (95 percent confidence interval [CI]: 1.37 to 4.73) and 7.43-fold greater than that of poor metabolizers (95 percent CI: 1.01 to 54.5), their identification by means of the DMP test may be particularly useful for subjects exposed to environmental and occupational carcinogens. The phenotype test used is similar to that of the debrisoquin test, but presents the advantage that DMP is a widely used, harmless drug with a faster and simpler urinary assay procedure.

Adolescent↗