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PubMed1998

Dextromethorphan and dextrorphan in rats: common antitussives--different behavioural profiles.

Dextromethorphan (DM), a widely used and well-tolerated centrally acting antitussive, has been tested in several clinical trials for its antiepileptic and neuroprotective properties. However, the use of DM in these new clinical indications requires higher doses than antitussive doses, which may therefore induce phencyclidine (PCP)-like side-effects (memory and psychotomimetic disturbances) through its metabolic conversion to the active metabolite dextrorphan (DX), a more potent PCP-like non-competitive antagonist at the N-methyl-D-aspartate (NMDA) receptor than DM. Thus, we compared the behavioural effects in rats of intraperitoneal administration of DM and DX on motor activity in an open field and on learning and memory in the Morris water maze. DM (20, 30, 40 mg/kg) produced a dose-dependent decrease in both locomotion and stereotyped behaviour with a slight ataxia for the highest dose. DX (20, 30, 40 mg/kg) induced a dose-dependent increase in locomotion and stereotypies (swaying, turning) with moderate ataxia. Assessments of learning and memory were performed with lower doses of DM (10, 20, 30 mg/kg) and DX (5, 10, 15 mg/kg) because of motivational deficits (40 mg/kg of DM, 20-40 mg/kg of DX) and motor disorders (30, 40 mg/kg of DX) in the cue learning procedure. DX (10, 15 mg/kg) impaired spatial learning with a long-lasting effect for the highest dose whereas 5 mg/kg of DX and DM (10-30 mg/kg) did not. Only 15 mg/kg of DX appeared to slightly impair working memory. DM (10-30 mg/kg) and DX (5-15 mg/kg) did not impair reference memory. Thus, the two antitussives DM and DX induced different behavioural effects suggesting sedative effects for DM and PCP-like effects for DX. However, PCP-like side-effects with DM remain possible through its metabolic conversion to DX, with very high doses and/or in extensive metabolizers and/or in aged subjects prone to cognitive dysfunction. Therefore, the identification of DM metabolism phenotype, an adapted prescription and a pharmacological modulation of the DM metabolism may avoid adverse effects.

Animals↗
PubMedDate not supplied

Pharmacokinetics of dextromethorphan and dextrorphan in epileptic patients.

The present report describes the pharmacokinetic characteristics of dextromethorphan (DM) and its main active metabolite dextrorphan (DX) in a group of epileptic patients receiving comedication. Patients were sequentially dosed with DM 40 mg/6 h (8 weeks) and 50 mg/6 h (8 weeks) while concurrent antiepileptic drugs were kept stable. During baseline period, patients were phenotyped with regard to their drug metabolizing capacity. At the end of each treatment period, timed plasma DM and DX levels were determined post-dose by HPLC. Urine and cerebrospinal fluid f1p4) samples were also collected. The pharmacokinetic parameters of DM showed a wide intersubject variation. The genetic polymorphism of DM metabolism was identified as the possible cause of the observed variability. For both DM and DX mean values for Cmax and AUC increased in a linear fashion with dose, while the mean values of tmax and t 1/2 were not dependent on dose. The mean values of CL/F and Vss/F for DM were also dose-dependent. 3-Methoxymorphinan, an N-demethylated metabolite of DM was detected in plasma and CSF of some patients and warrants further investigation as to its possible CNS effects. In conclusion, DM given in doses up to 50 mg/6 h can produce plasma and brain concentrations similar to the in vitro antiepileptic levels, without causing significant adverse effects.

Adult↗
PubMed2005

On-line solid phase extraction using the Prospekt-2 coupled with a liquid chromatography/tandem mass spectrometer for the determination of dextromethorphan, dextrorphan and guaifenesin in human plasma.

An on-line liquid chromatography/tandem mass spectrometry (LC-MS/MS) procedure, using the Prospekt- 2 system, was developed and used for the determination of the levels of the active ingredients of cough/cold medications in human plasma matrix. The experimental configuration allows direct plasma injection by performing on- line solid phase extraction (SPE) on small cartridge columns prior to elution of the analyte(s) onto the analytical column and subsequent MS/MS detection. The quantitative analysis of three analytes with differing polarities, dextromethorphan (DEX), dextrorphan (DET) and guaifenesin (GG) in human plasma presented a significant challenge. Using stable-isotope-labeled internal standards for each analyte, the Prospekt-2 on-line methodology was evaluated for sensitivity, suppression, accuracy, precision, linearity, analyst time, analysis time, cost, carryover and ease of use. The lower limit of quantitation for the on-line SPE procedure for DEX, DET and GG was 0.05, 0.05 and 5.0 ng mL(-1), respectively, using a 0.1 mL sample volume. The linear range for DEX and DET was 0.05-50 ng mL(-1) and was 5-5,000 ng mL(-1) for GG. Accuracy and precision data for five different levels of QC samples were collected over three separate days. Accuracy ranged from 90% to 112% for all three analytes, while the precision, as measured by the %RSD, ranged from 1.5% to 16.0%

Antitussive Agents↗
PubMed2000

Dextromethorphan and its metabolite dextrorphan block alpha3beta4 neuronal nicotinic receptors.

Dextromethorphan (DM), a structural analog of morphine and codeine, has been widely used as a cough suppressant for more than 40 years. DM is not itself a potent analgesic, but it has been reported to enhance analgesia produced by morphine and nonsteroidal anti-inflammatory drugs. Although DM is considered to be nonaddictive, it has been reported to reduce morphine tolerance in rats and to be useful in helping addicted subjects to withdraw from heroin. Here we studied the effects of DM on neuronal nicotinic receptors stably expressed in human embryonic kidney cells. Studies were carried out to examine the effects of DM on nicotine-stimulated whole cell currents and nicotine-stimulated (86)Rb(+) efflux. We found that both DM and its metabolite dextrorphan block nicotinic receptor function in a noncompetitive but reversible manner, suggesting that both drugs block the receptor channel. Consistent with blockade of the receptor channel, neither drug competed for the nicotinic agonist binding sites labeled by [(3)H]epibatidine. Although DM is approximately 9-fold less potent than the widely used noncompetitive nicotinic antagonist mecamylamine in blocking nicotinic receptor function, the block by DM appears to reverse more slowly than that by mecamylamine. These data indicate that DM is a useful antagonist for studying nicotinic receptor function and suggest that it might prove to be a clinically useful neuronal nicotinic receptor antagonist, possibly helpful as an aid for helping people addicted to nicotine to refrain from smoking, as well as in other conditions where blockade of neuronal nicotinic receptors would be helpful.

Animals↗
PubMed1992

Replenishment of brain adenosine triphosphate content by morphinan-type N-methyl-D-asparatate receptor antagonists, dextrorphan and dextromethorphan through the activation of adenylate kinase.

The in vitro effects of four N-methyl-D-aspartate (NMDA) receptor antagonists, dextrorphan, (DX, CAS 125-73-5), dextromethorphan, (DM, CAS 125-71-3), dizocilpine (CAS 77086-21-6) and (+/-) 2-amino-7-phosphonoheptanoate (AP-7, CAS 85797-13-3) on rat brain adenylate kinase (AK) have been studied. DM was the most active of the four compounds in increasing rat brain AK activity. DX was slightly less active than DM, while the most potent NMDA antagonist, dizocilpine was somewhat weaker than the above two morphinan analogs (DX and DM). For AP-7, the AK activity was unchanged. The results may indicate that a causal relation cannot be made between the activation of the AK by these compounds and their ability to act as NMDA antagonists. When DX was added, the Km and Vmax values of the enzyme for ADP as a substrate decreased and increased, respectively, possibly reflecting an affinity change for the enzyme-substrate interaction by DX. The observed increase in the AK activity by the morphinan-type NMDA antagonists in vitro might result in their preserving effects on cerebral neuron integrity under the conditions where cerebral energy metabolism is disturbed. This assumption was at least partly confirmed in in vivo tests in which DX, unlike dizocilpine, increased ATP content of the brain in mice under the influence of hypoxia exerted by i.v. injection of KCN.

2-Amino-5-phosphonovalerate↗
PubMed1987

Dextrorphan and levorphanol selectively block N-methyl-D-aspartate receptor-mediated neurotoxicity on cortical neurons.

Neocortical neurons in cell cultures prepared from fetal mice were impaled for intracellular recording. Dextrorphan (DX), a clinically tested dextrorotatory morphinan lacking opioid action, did not alter neuronal membrane potential or conductance, but produced a selective attenuation of N-methyl-D-aspartate (NMDA) responses; kainate and quisqualate responses were not affected. DX also antagonized morphological and chemical (lactate dehydrogenase efflux) evidence of cortical neuronal cell injury produced by toxic bath exposure to NMDA, quinolinate or glutamate, but did not affect toxic exposure to quisqualate or kainate. This selective antagonism of neurotoxicity was apparent at micromolar concentrations of DX with an ED50 of 13 to 17 microM. A similar, but less potent neuron-protective effect, was seen with the opioid levorotatory enantiomer of DX, levorphanol (ED50, 40 microM). The O-methyl derivative of DX, dextromethorphan, also antagonized NMDA and glutamate neurotoxicity, but with possibly lower efficacy than DX. The higher potency of DX over levorphanol suggests that this novel neuron-protective action is not mediated by classic opiate receptors; it may be mediated at the "sigma opiate"/phencyclidine site. If further studies establish that DX and related compounds retain neuron-protective efficacy in appropriate animal models, the established clinical safety record of DX and dextromethorphan may allow prompt investigation of the NMDA receptor-blockade strategy in certain neurological disease states.

Animals↗
PubMed1993

Dextromethorphan O-demethylation and dextrorphan glucuronidation in a French population.

The dextromethorphan (DMP) O-demethylation and the dextrorphan (DRP) glucuronidation distributions were studied in 120 French Caucasian subjects. After a single 25 mg DMP oral administration, DMP, free and total DRP concentrations were measured in 8h-urine collection, using an HPLC technique with fluorescent detection. The DMP and free DRP concentrations ratio, in log form, was used to estimate the oxidative demethylation phenotype of the subjects. Two different populations were found. The first one consisted of the extensive metabolizers (90.8%, 95% confidence interval from 85.6 to 95.9%) and the second one consisted of poor metabolizers (9.2%, 95% confidence interval from 4.0 to 14.4%). The antimode value of the distribution was estimated at approximately 0.7 corresponding to a ratio of 5. Moreover, this ratio was compared to the DMP and total DRP concentrations ratio, usually defined to DMP O-demethylation phenotyping. On the other hand, the glucuronide DRP concentration was calculated by subtracting the free DRP concentration from the total DRP concentration. Consequently, the free DRP and glucuronide DRP concentrations ratio was also used to estimate the DRP glucuronidation in the present population. This ratio in log form reflected the UDP-glucuronyltransferase(s) capacity(ies). This log ratio appeared to be normally distributed in the population studied. These results show that log DMP/free DRP ratio can be used, as well as log DMP/total DRP ratio, to determine the oxidative phenotype of subjects and that the DRP conjugation does not exhibit any apparent genetic polymorphism.

Administration, Oral↗
PubMed1999

Evaluation of the reinforcing properties and phencyclidine-like discriminative stimulus effects of dextromethorphan and dextrorphan in rats and rhesus monkeys.

RATIONALE: Dextromethorphan (DXM) and its metabolite, dextrorphan (DXO) have neuroprotective and anticonvulsant properties through their activity as N-methyl-D-aspartate (NMDA) receptor channel blockers. Based on this receptor activity, coupled with reports of DXM abuse, both were evaluated for abuse potential and phencyclidine (PCP)-like behavioral effects in two animal models. OBJECTIVES AND METHODS: The discriminative stimulus properties of DXO and DXM were tested in rats (3-56 mg/kg DXM, i.p. and 2.2-40.9 mg/kg DXO, i.p.) and rhesus monkeys (0.3-10 mg/kg DXM, i.m. and 0.25-8.0 mg/kg DXO, i. m.) trained to discriminate PCP from saline using a standard two-lever drug-discrimination paradigm under a fixed-ratio (FR) schedule of food reinforcement. In a second set of experiments, i.v. self-administration of DXO (10-100 microg/kg/infusion) and DXM (10-1000 microg/kg/infusion) were tested under a FR schedule of reinforcement in monkeys trained to lever press for infusions of PCP during daily 1-h sessions. RESULTS: In rats, both DXM and DXO produced a dose-dependent substitution for PCP. When tested in monkeys, DXM yielded partial (1 monkey) and full (2 monkeys) substitution for PCP, while DXO substituted fully for PCP in all four subjects tested. In the self-administration study, in five of the six subjects, at least one dose of DXM served as a positive reinforcer, maintaining infusion rates above those for saline. For DXO, at least one dose maintained infusion numbers well above mean saline infusion numbers in all subjects. CONCLUSIONS: Taken together, these data show that DXM has some PCP-like effects in rats and monkeys, but that they are more reliably produced by its metabolite, DXO. Thus, high doses of DXM may have some PCP-like abuse potential in humans but this potential may be associated with, or enhanced by, metabolism of DXM to DXO.

Animals↗
PubMed2003

Determination of dextromethorphan and its metabolite dextrorphan in human urine by capillary gas chromatography without derivatization.

A sensitive, simple and accurate method was developed for determination of dextromethorphan (DM) and dextrorphan (DT) in human urine by capillary gas chromatography without derivatization. After an oral dose of 30 mg DM, urine samples were collected and extracted, then analyzed on 0.22 mmx17 m HP-1 capillary column. DM and its metabolite DT were analyzed simultaneously with good separation. Docosane was used as the internal standard (I.S.). The detector used was flame ionization detector (FID). There was a linear relationship between peak area ratios of analytes to I.S. and concentration of analytes over the concentration range 0.37-7.38 micromol/l for DM and 0.39-77.8 micromol/l for DT. The recovery was 88.1 approximately 103.9% for DM and 86.7 approximately 96.8% for DT. The within-day and between-day coefficients of variation were less than 7.4 and 7.3% (RSD) for the assay of DM and DT in urine, respectively. The limits of detection (LOD) were 0.30 micromol/l for DM and 0.16 micromol/l for DT. The limits of quantitation (LOQ) were 0.37 micromol/l (RSD<6%) for DM and 0.39 micromol/l (RSD<7%) for DT. The method has been applied to determine the oxidative phenotypes of cytochrome P450 2D6 (CYP2D6) in a Chinese population with metabolic ratio of DM in human urine.

Adolescent↗