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PubMedDate not supplied

Dextromethorphan metabolism in Jordanians: dissociation of dextromethorphan O-demethylation from debrisoquine 4-hydroxylation.

The concentrations of dextromethorphan (DM) and its metabolites dextrorphan (DRP), 3-methoxymorphinan (MM) and 3-hydroxymorphinan (HM) were measured in 8 h urine samples from 266 unrelated healthy Jordanian subjects following oral administration of 30 mg dextromethorphan hydrobromide and using a rapid, sensitive and precise HPLC method with fluorometric detection. The frequency of the 'poor' metabolizer status of DM-O-demethylation as judged by log DM/DRP was found to be 6.8% with a 95% confidence interval of 3.8-9.8%. There was a strong correlation between log DM/DRP and log total non-O-demethylated compounds (NODM)/total O-demethylated metabolites (ODM) metabolic ratios (r = 0.96, P < 0.01). However, one subject with log DM/DRP of 0.05 that classifies him as a poor metabolizer was found to have a log NODM/ODM of -0.73 which is in the range of extensive metabolizer status suggesting the presence of another cytochrome P450 isoenzyme involved in dextromethorphan O-demethylation. Dextromethorphan N-demethylation to 3-methoxymorphinan was detected in 55.3% of individuals. Furthermore, a dissociation between dextromethorphan O-demethylation and debrisoquine (D) 4-hydroxylation has been observed. Among the 116 subjects phenotyped with both dextromethorphan and debrisoquine, 7 were poor metabolizers of both, three were poor metabolizers of debrisoquine and extensive metabolizers of dextromethorphan whilst 4 were poor metabolizers of dextromethorphan and extensive metabolizers of debrisoquine, one of whom was reclassified as an extensive metabolizer of dextromethorphan using log NODM/ODM to characterize dextromethorphan metabolizer status.

Adolescent↗
PubMed2005

The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of dextromethorphan.

In a previous study, we demonstrated that a dextromethorphan analog, dimemorfan, has neuroprotective effects. Dextromethorphan and dimemorfan are high-affinity ligands at sigma1 receptors. Dextromethorphan has moderate affinities for phencyclidine sites, while dimemorfan has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of dimemorfan. Kainate (KA) administration (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with dimemorfan (12 or 24 mg kg(-1)) reduced seizures in a dose-dependent manner. Dimemorfan pre-treatment also attenuated the KA-induced increases in c-fos/c-jun expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of dimemorfan were comparable to those of dextromethorphan. The anticonvulsant action of dextromethorphan or dimemorfan was significantly counteracted by a selective sigma1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or dimemorfan is, at least in part, related to sigma1 receptor-activated modulation of AP-1 transcription factors. We asked whether dimemorfan produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with dimemorfan showed no behavioral side effects. Our results suggest that dimemorfan is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions.

Animals↗
PubMed2005

Dextromethorphan to dextrorphan urinary metabolic ratio does not reflect dextromethorphan oral clearance.

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 < 0.001), 6-h (r = 0.67; p < 0.001), and 8-h (r = 0.74; p < 0.001) dextromethorphan to dextrorphan serum ratios. Assuming an effect size of 30%, the number of volunteers required for crossover and cross-sectional studies using the urinary metabolic ratio as the CYP2D6 index was calculated to be 56 and 524, respectively, whereas 14 and 60 subjects are needed if oral clearance is used. Considering the required sample size and the low correlation with oral clearance, urinary metabolic ratio is not recommended as the primary outcome variable in studies requiring the detection of modest changes in CYP2D6 activity.

Administration, Oral↗
PubMed1990

Pharmacokinetic comparison of a dextromethorphan-salbutamol combination tablet and a plain dextromethorphan tablet.

We compared in this double-blind crossover study the bioavailability of dextromethorphan from a dextromethorphan-salbutamol combination tablet (Redol comp) and from a plain dextromethorphan tablet (Extuson) by determining dextrorphan concentrations after single-dose oral administration in 10 healthy volunteers. The absorption of salbutamol from the combined preparation was also determined. The absorption of dextromethorphan was slightly faster from the plain dextromethorphan preparation. The peak concentration of dextrorphan was achieved at 1.5 h after Extuson and at 2 h after Redol comp (1,053.0 +/- 366.5 ng/ml and 901.5 +/- 210.9 ng/ml, NS). AUC0-12 values of dextrorphan were 4,315.6 +/- 295.0 (ng/ml)h after Extuson and 3,983.8 +/- 205.6 (ng/ml)h after Redol comp (p less than 0.05). Salbutamol was well absorbed from the combined preparation and the peak concentration was achieved at 3 h (6.57 +/- 2.95 ng/ml). Four subjects reported side-effects typical for salbutamol after the combination tablet. No side-effects were reported after the plain dextromethorphan tablet. On the basis of the present study, we conclude that the absorption of dextromethorphan from the preparations tested is almost equal and the dextromethorphan-salbutamol combination can be administered in tablet form for the treatment of cough.

Adult↗
PubMed1995

The dextromethorphan defense: dextromethorphan and the opioid screen.

OBJECTIVE: To determine whether a single oral dose of dextromethorphan produces a falsely positive qualitative urine opioid screen. METHODS: A prospective, randomized, triple-blind, placebo-controlled, crossover exposure study design was used. Twenty adult volunteers participated. All were without routine medications, not pregnant or lactating, without known sensitivity to dextromethorphan, and negative for urine toxicologic screening immediately prior to testing. These volunteers underwent three separate urine Enzyme-Multiplied Immunoassay Technique (EMIT) opioid screens. Each screen was performed six hours after the subject had ingested a single liquid medication, either dextromethorphan, codeine, or placebo. Each volunteer took all three medications randomly, at least 72 hours apart. Half of the volunteers took the standard adult dose of dextromethorphan (20 mg), while the other half ingested twice this amount (40 mg). The amounts of codeine (30 mg) and sucrose placebo (10 mL) remained constant. RESULTS: For these young adults (mean age +/- SD = 30.7 +/- 2.8 years), all urine EMIT assays six hours after ingestion of dextromethorphan, at both dosage levels, were negative for opioids and all other drugs. All assays after codeine and placebo ingestion were positive and negative for opioids, respectively. CONCLUSION: Although dextromethorphan is structurally similar to opioid drugs, the ingestion of a single normal (or even twice normal) dose of dextromethorphan is not likely to produce a falsely positive six-hour urine opioid EMIT screen.

Adult↗
PubMed1987

Antitussive effect of dextromethorphan and dextromethorphan-salbutamol combination in healthy volunteers with artificially induced cough.

The antitussive effects of dextromethorphan (30 mg) + salbutamol (2 mg), dextromethorphan (30 mg) alone and placebo on artificial cough induced by citric acid were compared in 19 healthy non-smoking volunteers in a double-blind crossover study. The method using inhaled citric acid with increasing concentrations to establish the cough threshold level showed an acceptable reproducibility and proved to be suitable for comparison of antitussive drugs. The cough threshold level was assessed before as well as 90 and 180 min after each medication. After placebo the cough threshold level showed no statistically significant rise. However, significant rises were shown following dextromethorphan (p less than 0.001) and the dextromethorphan-salbutamol combination (p less than 0.001). Between the treatments significant differences were shown in favour of the dextromethorphan-salbutamol combination. The results indicate that salbutamol has antitussive action enhancing the effect of plain dextromethorphan.

Adult↗
PubMed1986

The treatment of acute transient cough: a placebo-controlled comparison of dextromethorphan and dextromethorphan-beta 2-sympathomimetic combination.

The efficacy of an antitussive-beta 2-sympathomimetic combination (dextromethorphan-salbutamol) was compared with that of a plain antitussive (dextromethorphan) and a placebo in a double-blind trial in 108 out-patients with cough associated with acute respiratory infection. The dextromethorphan-salbutamol combination was superior to dextromethorphan or placebo in the suppression of cough at night, although a spontaneous improvement occurred in all treatment groups during the 4-day treatment period. No statistically significant differences between the treatments were shown in the symptom scores for the cough frequency and severity during the day, sputum quantity or ease of expectoration. A significant improvement in cough during the day was observed in all treatment groups. The results suggest that the use of antitussives is usually unnecessary; the only indication might be symptomatic relief, especially at night. An antitussive combined with a beta 2-sympathomimetic might be the most effective treatment in this type of cough.

Acute Disease↗
PubMed1998

The stimulus properties of two common over-the-counter drug mixtures: dextromethorphan + ephedrine and dextromethorphan + diphenhydramine.

Two groups of rats were trained in a two-choice drug discrimination procedure under a fixed-ratio 10 schedule of food reinforcement. One group of rats (n=12) was trained to discriminate the presence and absence of a drug mixture containing 10 mg/kg dextromethorphan + 10 mg/kg diphenhydramine. The other group of rats (n=12) was trained to discriminate the presence and absence of another drug mixture containing 10 mg/kg dextromethorphan + 10 mg/kg ephedrine. Cross-generalization tests conducted with each of the stimulus elements demonstrated that (1) the drug mixtures were not perceived as new entities distinct from their component elements and (2) the stimulus element saliency may be a factor determining the nature of discriminative control by drug mixtures. Cross-generalization tests conducted with the psychomotor stimulants, cocaine and amphetamine, engendered complete generalization to the training cues in both groups, whereas, pentobarbital engendered predominantly saline- or default-lever responding. These data suggest a potential abuse liability for both of these common over-the-counter drug mixtures and cautions against the use of such combinations in pediatric patients.

Adrenergic Agents↗
PubMed2004

Dextromethorphan-associated epidural patient-controlled analgesia provides better pain- and analgesics-sparing effects than dextromethorphan-associated intravenous patient-controlled analgesia after bone-malignancy resection: a randomized, placebo-controlled, double-blinded study.

UNLABELLED: Pain after bone malignancy surgery is intense and requires large amounts of analgesics. The augmented antinociceptive effects of dextromethorphan (DM), a N-methyl-D-aspartate receptor antagonist, were demonstrated previously. We assessed the use of postoperative patient-controlled epidural analgesia (PCEA) or IV patient-controlled analgesia (PCA) in patients undergoing surgery for bone malignancy under standardized combined general and epidural anesthesia with or without DM. Patients (n = 120) were randomly allocated to receive PCEA (ropivacaine 3.2 mg plus fentanyl 8 microg/dose) or IV-PCA (morphine 2 mg/dose) postoperatively, starting at subjective visual analog scale pain intensity >or=4 of 10 for up to 96 h. Placebo or DM 90 mg orally (30 patients/group/set) was given in a double-blinded manner before surgery and for 2 days afterwards. Diclofenac 75 mg IM was available as a rescue drug. DM patients used PCA and rated their pain >50% less than their placebo counterparts in each set, especially during the first 2 postoperative days (P < 0.01). Hourly and overall maximal pain intensity among PCEA patients was approximately 50% less than in the IV-PCA set (P < 0.01). Diclofenac was used 42% less (P < 0.01) by the PCA-DM patients compared with their placebo counterparts. Seven PCEA-DM and 11 IV-PCA-DM individuals reported having side effects compared with 44 in the PCEA-placebo and the IV-PCA-placebo groups (P < 0.01). Time to first ambulation was similar with both analgesia techniques but shorter among the DM-treated patients compared with the placebo recipients (1.5 +/- 0.8 versus 2.1 +/- 1.1 days, P = 0.02). Thus, DM afforded better pain control and reduced the demand for analgesics, augmented the PCEA effect versus IV-PCA, and was associated with minimal untoward effects in each analgesia set. DM patients ambulated earlier than placebo recipients. IMPLICATIONS: Patients undergoing bone-malignancy surgery under combined general and epidural anesthesia received randomly patient-controlled epidural analgesia (PCEA) or IV patient-controlled analgesia (PCA) postoperatively and dextromethorphan (DM) 90 mg or placebo double-blindly for 3 days (n = 30/group/set). The DM effect was recorded with minimal untoward effects: it afforded better pain control and reduced the demand for analgesics compared with the placebo, especially when associated with PCEA. DM patients ambulated earlier than placebo recipients.

Adult↗
PubMed1998

[Effects of oxatomide, H1-antagonist, on postinfectious chronic cough; a comparison of oxatomide combined with dextromethorphan versus dextromethorphan alone].

H1 antihistamines have been shown to have antitussive effects in patients with asthma and postnasal drip. In Japan, no study has been performed to determine whether orally administered oxatomide, H1 antihistamine, can reduce the chronic cough seen in patients with post-upper-airway infection (postinfection). Patients who had chronic cough of more than three weeks' duration and a history of post-upper-airway infection took part in the study. None had any history of nasal disease, gastroesophageal reflux, bronchial asthma, or other chronic pulmonary disease. All patients were non-smokers, and none used ACE inhibitors. They had normal CRP concentrations, peripheral white blood cell and eosinophil counts, serum IgE concentrations, titers of cold agglutinins and antibodies to Mycoplasma pneumoniae, chest roentgenograms, and respiratory function tests. A prospective randomized, open design was used. The effect of one week of treatment with dextromethorphan (D) or with D plus oxatomide (D + O) on the severity of cough, as estimated by cough diary, were examined. Twenty-two patients entered the study, and 20 were eligible for efficacy and side-effect analyses. Nine patients receiving D and 11 receiving D + O completed the protocol. Patients' characteristics before the start of the study, such as severity and duration of cough, and laboratory data, were not significantly different between the two groups. From trial day 5 to 7, improved rates of cough were significantly higher with D + O than with D alone (p < 0.05). Combination therapy with oxatomide and dextromethorphan reduces subjective perception of cough as estimated by cough diary. These results suggest that oxatomide, H1 antihistamine may improve chronic cough in patients with post-upper-airway infection.

Adult↗
PubMed2001

Comparative contribution to dextromethorphan metabolism by cytochrome P450 isoforms in vitro: can dextromethorphan be used as a dual probe for both CTP2D6 and CYP3A activities?

Dextromethorphan (DXM) is a widely used probe drug for human CYP2D6 activity both in vitro and in vivo. In humans, DXM is metabolized to dextrorphan (DXO), as well as 3-methoxymorphinan (MEM) and 3-hydroxymorphinan (HYM). The formation of MEM has been attributed primarily to CYP3A4, and the use of DXM has been debated as a simultaneous probe for CYP3A4 and CYP2D6 activities. Recently, we found that highly purified CYP2D6 has significant DXM N-demethylase activity in addition to its well known DXM O-demethylase activity. Therefore, we desired to further compare the contribution to DXM metabolism by individual human cDNA-expressed cytochromes P450, including 2C8, 2C9, 2C18, 2C19, 2D6, 2B6, and 3A4. Metabolites were quantified following separation by high-pressure liquid chromatography and apparent Michaelis-Menten constants determined for the appearance of DXO and MEM. Intrinsic clearance values were estimated for each P450 and normalized using the average percentage content and relative activity factor approaches for comparison. Simplified kinetic models (when [S] << K(m), V(max)/K(m) = V(o)/[S]) were used at fixed DXM concentrations of 20 (for DXM N-demethylation) and 0.2 microM (for DXM O-demethylation), as well as 2 microM to mimic plasma DXM concentrations in human extensive metabolizers. The results confirm that CYP2D6 contributes at least 80% to the formation of DXO, and CYP3A4 contributes more than 90% to the formation of MEM. All of our in vitro results are consistent and indicate that DXM as a marker for monitoring both CYP2D6 and CYP3A activities is practical in an average human or human liver microsomal preparation.

Antitussive Agents↗
PubMed1990

The treatment of heroin addicts with dextromethorphan: a double-blind comparison of dextromethorphan with chlorpromazine.

According to the hypothesis that the development of physical dependence on and tolerance to opiates depends on the inhibition by opiates of L-asparaginase and L-glutaminase activities in the brain, and the blockade by opiates of the aspartatergic/glutamatergic receptors especially NMDA, four female and fourty-four male heroin addicts were included in a double-blind clinical trial. Four mg chlorpromazine (CPZ) was administered every hour and 10 mg diazepam (DIA) every 6 hours to a group consisting of two female and nineteen male inpatients. The remaining subjects received 15 mg non-opioid antitussive dextromethorphan (DM) instead of CPZ. The withdrawn addicts were controlled twice a day and yawning, lacrimation, rhinorrhoea, perspiration, goose flesh, muscle tremor, dilated pupils, anorexia, joint and muscle aches, restlessness, insomnia, emesis, diarrhea, craving and rejection of smoking as abstinence syndrome signs were observed and rated on a scale of 1, 2 and 3 points according to their intensity. All signs, except perspiration and emesis, were significantly less intense in the group given DM + DIA than CPZ + DIA. The other plus points included the immediate stop of craving and the early onset of smoking in DM + DIA group. The results are considered to be supporting evidence for the hypothesis emphasizing the blockade of NMDA receptors by opiates in opiate addiction. Furthermore, the decrease caused by non-opioid NMDA antagonists in the responsiveness of NMDA receptors appears very promising for the treatment of opiate addicts.

Adult↗
PubMed1994

Discriminative stimulus effects of dextromethorphan in the rat.

This study was performed to characterize pharmacologically the discriminative stimulus effects of dextromethorphan, an antitussive that binds with high affinity to a subtype of sigma site in the brain. Dextrorphan, a metabolite of dextromethorphan, has phencyclidine (PCP)-like effects. Therefore, training was conducted with dextromethorphan injected by the SC route, which minimizes dextrorphan formation compared to the IP route. The training dose used, 30 mg/kg, by the SC route did not occasion selection of the PCP-appropriate choice lever in rats discriminating IP injections of 2.0 mg/kg PCP from saline. (In contrast, by the IP route the ED50 of dextromethorphan for PCP-appropriate lever selection was 21.7 mg/kg). In rats discriminating 30 mg/kg (SC) of dextromethorphan from distilled water, dextromethorphan was slightly more potent SC than it was IP (ED50s for dextromethorphan-appropriate lever selection: 8.5 and 14.9 mg/kg, respectively). These animals generalized dose-dependently and completely to PCP and to other PCP-receptor ligands, but selected the vehicle-appropriate choice lever when tested with sigma-site ligands, mu-opioid agonists, and naltrexone. Concurrent administration of naltrexone or sigma-site ligands with 30 mg/kg dextromethorphan did not block dextromethorphan-appropriate responding. These results show that the discriminative effects of SC dextromethorphan are PCP-like and are not mediated by the high-affinity dextromethorphan binding site or by the mu-opioid receptor. Because little dextrorphan is formed when dextromethorphan is given SC and because dextromethorphan itself has low affinity for the PCP receptor, the discriminative effects of SC dextromethorphan probably are mediated by a recognition site related closely to but different from the PCP receptor.

Animals↗
PubMed1996

The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans.

OBJECTIVES: We studied the disposition of dextromethorphan in extensive and poor metabolizer subjects, as well as the effect of this polymorphism on the antitussive action of dextromethorphan. METHODS: Six extensive metabolizers were studied on four occasions: (1) after 30 mg dextromethorphan, (2) after 30 mg dextromethorphan 1 hour before 50 mg quinidine, (3) after placebo, and (4) after 50 mg quinidine. Six poor metabolizers were studied on two occasions: (1) after 30 mg dextromethorphan and (2) after placebo. Blood and urine were collected over 168 hours and assayed for dextromethorphan, total (conjugated and unconjugated) dextrorphan, 3-methoxymorphinan, and total 3-hydroxymorphinan. On each occasion at each blood sampling time, capsaicin was administered as an aerosol to provoke cough. RESULTS: Dextromethorphan area under the plasma concentration-time curve (AUC) was 150-fold greater in the poor metabolizers than in the extensive metabolizers, and quinidine increased the AUC in extensive metabolizers 43-fold. The median dextromethorphan half-life was 19.1 hours in poor metabolizers, 5.6 hours in extensive metabolizers given quinidine, and 2.4 hours in extensive metabolizers. For dextrorphan (as total), the AUC was reduced 8.6-fold in poor metabolizers; quinidine had no effect on the AUC. The median half-life was 10.1 hours in poor metabolizers, 6.6 hours in extensive metabolizers given quinidine, and 1.4 hours in extensive metabolizers. The apparent partial clearance of dextromethorphan to dextrorphan was 1.2 L/hr in poor metabolizers, 78.5 L/hr in extensive metabolizers given quinidine, and 970 L/hr in extensive metabolizers. There was a strong (r2 = 0.82) and significant (p < 0.01) positive correlation between the prestudy urinary metabolic ratios and the partial clearances of dextromethorphan to dextrorphan. There was very large intersubject variability in responsiveness to capsaicin. There was no difference in the capsaicin-induced cough frequency in the three groups. Dextromethorphan had no antitussive effect in this experimental cough model. CONCLUSION: The disposition of dextromethorphan was substantially influenced by CYP2D6 status. Capsaicin may not be an ideal agent in experimental cough studies.

Adult↗
PubMed1995

Effects of route of administration on dextromethorphan pharmacokinetics and behavioral response in the rat.

One of the potential problems of using dextromethorphan as a neuroprotective or anticonvulsant agent is the phencyclidine-like behavioral effects that have been attributed to its major metabolite dextrorphan. Because previous behavioral studies of dextromethorphan have generally failed to consider metabolic conversion to this metabolite, the present studies were conducted to examine the effects of route of administration on dextromethorphan pharmacokinetics and locomotor activity in the rat. The bioavailability of dextromethorphan was 1.3-fold lower and the formation of dextrorphan and other metabolites was 3-fold greater after i.p. injection of 30 mg/kg of dextromethorphan as compared to the s.c. route, indicating substantial effect of first-pass metabolism. Plasma dextromethorphan was correlated with brain dextromethorphan (r = 0.84, P < .001), and the brain/plasma concentration ratio was about 6.5. Plasma-free dextrorphan, but not conjugated dextrorphan, was correlated with brain dextrorphan (r = 0.97, P < .001). Tmax of brain dextrorphan was earlier, and Cmax was higher after i.p. injection of dextromethorphan than s.c. administration (60 min vs. 120 min and 1.0 nmol/g vs. 0.2 nmol/g). Dextromethorphan (60 mg/kg i.p.) increased locomotor activity in the rat 60 min postdose, whereas the same dose of dextromethorphan administered by s.c. injection was without effect. These data demonstrate the route-specific effects on the disposition of dextromethorphan and dextrorphan in rat plasma and brain, as well as the behavioral consequence of the difference.

Animals↗
PubMed1994

Characterization of dextromethorphan N-demethylation by human liver microsomes. Contribution of the cytochrome P450 3A (CYP3A) subfamily.

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)

Adult↗
PubMed1996

A pilot study of dextromethorphan in naloxone-precipitated opiate withdrawal.

Dextromethorphan and its metabolite dextrophan antagonize N-methyl-D-aspartate (NMDA)-mediated activity in pre-clinical studies. We examined dextromethorphan's effects on naloxone-precipitated opiate withdrawal in opiate-dependent subjects stabilized on 25 mg of methadone. Subjects received challenges on three different days with 0.4 mg of intramuscular naloxone. Pretreatment 1 h before naloxone was with dextromethorphan in a double-blind, balanced, randomized design with either placebo, dextromethorphan 60 mg, or dextromethorphan 120 mg for six subjects; and placebo, dextromethorphan 120 mg, or dextromethorphan 240 mg for five subjects. There was considerable inter-individual variability in the response to dextromethorphan, but no net attenuation by dextromethorphan on any withdrawal measure assessed. Two of three subjects detoxified from methadone with dextromethorphan 60 mg orally every 4 h demonstrated considerable withdrawal.

Adult↗