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PubMed1999

Assessment of CYP2D6 and CYP2C19 activity in vivo in humans: a cocktail study with dextromethorphan and chloroguanide alone and in combination.

OBJECTIVES: Dextromethorphan and chloroguanide (INN, proguanil) are used as prototypic phenotyping substrates of polymorphically expressed CYP2D6 and CYP2C19 in humans. We determined whether the dextromethorphan/dextrorphan and chloroguanide/cycloguanil metabolic ratios, obtained after administration of the parent drugs either alone or in combination, are equivalent. METHODS: Thirty-six healthy male volunteers received single oral doses of 80 mg dextromethorphan and 200 mg chloroguanide during a three-period, randomized crossover study. Plasma and urine were collected to calculate metabolic ratios and analyze the disposition kinetics of the probe drugs. RESULTS: All subjects were extensive metabolizers for both CYP2D6 and CYP2C19. Chloroguanide kinetics and urinary metabolic ratio were not altered after dextromethorphan administration. Dextromethorphan urinary metabolic ratio increased from -2.52 +/- 0.67 to -2.03 +/- 0.58 (P < .001) in the presence of chloroguanide. This was caused by an increase of dextromethorphan without a significant change of dextrorphan in both urine and plasma. Inhibition of CYP3A-dependent biotransformation of dextromethorphan to methoxymorphinan did not appear to be responsible for this change because the log(dextromethorphan/methoxymorphinan) urinary ratio, an index of CYP3A activity, did not significantly change during chloroguanide coadministration. The chloroguanide and dextromethorphan metabolic ratio determined from urine collection correlated with the corresponding metabolic ratio determined from plasma obtained 3 hours after oral administration. CONCLUSION: When CYP2D6 and CYP2C19 activity are assessed, dextromethorphan and chloroguanide cannot be associated in a cocktail because chloroguanide increases the dextromethorphan metabolic ratio. CYP2D6 and CYP2C19 activity can be determined from a blood sample drawn 3 hours after oral administration of dextromethorphan and chloroguanide, respectively.

Administration, Oral↗
PubMed1998

Psychotropic effects of dextromethorphan are altered by the CYP2D6 polymorphism: a pilot study.

Dextromethorphan is a nonopioid antitussive metabolized by cytochrome P450 2D6 (CYP2D6) to an active metabolite, dextrorphan. CYP2D6 is polymorphically expressed in humans, with 5 to 10% of Caucasians being homozygous deficient for the active form of the enzyme. In a pilot study, the authors investigated the pharmacologic effects of dextromethorphan in individuals phenotyped and genotyped as extensive metabolizers (EMs, N = 4) and poor metabolizers (PMs, N = 2) of CYP2D6 substrates. Dextromethorphan doses ranged from 0 to 6 mg/kg based on individual subject tolerance. All EMs tolerated 3 to 6 mg/kg dextromethorphan, whereas PMs barely tolerated 3 mg/kg dextromethorphan and therefore received lower doses. As shown in previous studies, plasma kinetics show profound differences in dextromethorphan metabolism between EMs and PMs. Dextromethorphan produced qualitatively and quantitatively different objective and subjective effects in the two groups. Objectively, PMs had greater psychomotor impairment, as measured by a joystick tracking task, compared with EMs on 3 mg/kg dextromethorphan (mean performance +/- SE, 95+/-0.5% for EMs vs. 86+/-6% for PMs; p < 0.05). At this dose, EMs also reported greater abuse potential compared with PMs (p < 0.05), and PMs reported greater sedation and dysphoria compared with EMs (p < 0.01). These data provide preliminary evidence that dextrorphan contributes to dextromethorphan abuse liability, and therefore PMs may be less likely to abuse dextromethorphan.

Adult↗
PubMed2006

Inhibition of the serotonin-induced inward current by dextromethorphan in rat nodose ganglion neurons.

Dextromethorphan is one of the most widely used antitussives for the treatment of cough. In the present study, we investigated the effect of dextromethorphan on 5-hydroxytryptamine (5-HT)-induced currents in acutely dissociated rat nodose ganglion neurons using nystatin-perforated patch-clamp recording configuration. The 5-HT-induced current was inhibited by the 5-HT(3) receptor antagonist tropisetron, while the selective 5-HT(3) receptor agonist 1-(m-chlorophenyl)-biguanide hydrochloride (mCPBG) induced a similar current. Dextromethorphan reversibly and concentration-dependently inhibited the 5-HT-induced inward current. The inhibition did not appear to be voltage-dependent. Both the peak and steady-state 5-HT-induced currents were inhibited by dextromethorphan, although the peak current was more sensitive to dextromethorphan block. The IC(50) values for the inhibition of peak and steady currents evoked by 3 muM 5-HT were 16.4 and 34.4 muM, respectively. In the presence of 10 muM dextromethorphan, the concentration-response curve for 5-HT was shifted to the right without changing the maximum response, while high concentrations reduced the maximum current. The 5-HT EC(50) values in the presence of 0, 10, 30 and 60 muM dextromethorphan were 4.3, 6.8, 15.5 and 40.6 muM, respectively. The results indicate that dextromethorphan inhibits the 5-HT-induced current of rat nodose ganglion neurons, and further suggest that dextromethorphan at a low concentration acts as a competitive inhibitor of 5-HT(3) receptors.

Animals↗
PubMed1999

Narrow beneficial effect of dextromethorphan on levodopa-induced motor response alterations in an experimental model of parkinsonism.

The effects of acute and chronic dextromethorphan on levodopa-induced motor response alterations have been studied in rats with unilateral lesion of nigrostriatal pathway induced by 6-hydroxydopamine (6-OHDA). Male Sprague-Dawley rats received a 6-OHDA injection (8 microg) into the left medial forebrain bundle. To validate the effect of acute dextromethorphan administration, groups of rats were treated with levodopa (25 mg/kg, twice daily) for 22 days. On day 23, animals received dextromethorphan (20, 30 or 40 mg/kg) immediately before levodopa. In a second set of experiments, lesioned rats were concomitantly treated with levodopa plus dextromethorphan (20, 30 or 40 mg/kg, twice at day) for 22 consecutive days in order to investigate the potential effect of chronic dextromethorphan administration in preventing the decrease in the duration of motor response. As expected, the duration of the motor response to levodopa had significantly decreased by the 22nd day of levodopa in each group of treatment. Acute administration of dextromethorphan on day 23 reversed the reduction in the duration of the levodopa response only when administered at the lowest dose used in the present study (20 mg/kg) (p<0.05). Chronic administration of dextromethorphan concomitant to levodopa did not prevent levodopa effect showing a significant decrease on motor response duration (124+/-4 on day 1 vs. 88+/-16 on day 22, p<0.05, 30 mg/kg, twice a day). Our results indicate that in parkinsonian rats dextromethorphan is not a useful drug to prevent levodopa-induced motor alterations, however, low doses of dextromethorphan may be beneficial to reverse these alterations in motor response.

Animals↗
PubMed2000

The effect of dextromethorphan, alone or in combination with ibuprofen, on postoperative pain after minor gynaecological surgery.

BACKGROUND: Experimental studies have demonstrated that peripheral tissue injury may lead to hyperexcitability of nociceptive neurones in the dorsal horn, in part mediated by N-methyl-D-aspartate (NMDA)-receptor mechanisms. Sensitisation of dorsal horn neurones may be an important contributor to postoperative pain. The aim of the present study was to investigate the effect of the NMDA-receptor antagonist dextromethorphan on pain after minor gynaecological surgery, and to evaluate a potential additive effect with ibuprofen. METHODS: In a double-blind, placebo-controlled study, 100 patients scheduled for elective termination of pregnancy were randomised to receive placebo, oral ibuprofen 400 mg, oral dextromethorphan 120 mg, or a combination of ibuprofen 400 mg and dextromethorphan 120 mg, 1 h before surgery. Pain and analgesic requirements were assessed 0.5, 1 and 2 h after operation. RESULTS: We observed no effect of dextromethorphan on visual analogue scale (VAS) pain scores or analgesic consumption, and no additive or synergistic analgesic effects between ibuprofen and dextromethorphan. Ibuprofen reduced pain scores compared with placebo, and analgesic consumption compared with both placebo and dextromethorphan. The combination of ibuprofen and dextromethorphan increased preoperative nausea compared with both placebo and ibuprofen, whereas no statistically significant side effects were observed with dextromethorphan alone. CONCLUSION: No analgesic effects of oral dextromethorphan 120 mg on pain after surgical termination of labour, and no additive analgesic effects when combined with ibuprofen 400 mg, were observed. Ibuprofen reduced both VAS pain scores and analgesic consumption compared with placebo.

Adult↗
PubMed2002

Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind-up of the second pain response in healthy male volunteers.

AIMS: The aim of this study was to assess the efficacy of dextromethorphan and ketamine relative to placebo on the acute nociceptive threshold and wind-up of second pain response in healthy male volunteers. METHODS: The trial was a randomized, double-blind, placebo-controlled, three period crossover, double dummy design in 12 healthy male volunteers. During each of the three periods (which were separated by a 1 week washout period) each volunteer received either a single oral dose of 0.7 mg kg(-1) dextromethorphan and placebo to ketamine, or placebo to dextromethorphan followed by a single intravenous injection of 0.375 mg kg(-1) ketamine, or placebo to both dextromethorphan and ketamine. The trial did not schedule administration of both ketamine and dextromethorphan together. Acute nociceptive thresholds and wind-up of second pain were measured in the skin of the thenar eminence of the ventral surfaces of the right and left hands, using a SOMEDIC thermotest apparatus, before and at the estimated tmax for dextromethorphan (i.e. 2.15 h). Blood pressure and heart rate were also monitored before dosing and after the dosing regimen. RESULTS: Neither dextromethorphan nor ketamine had any significant effect on acute nociceptive thresholds on either hand (P>0.05). Moreover, dextromethorphan was without any significant effect (P>0.05) on the wind-up of the second pain response on either hand. The lsmean number of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 15.84 vs 16.48 (-5.52, 4.24) and 11.75 vs 15.25 (-11.89, 4.90) for left- and right-hand, respectively, following dextromethorphan administration. In contrast ketamine produced significant reductions in wind-up to second pain in both the left and right hands (P=0.0002 and 0.0386, respectively). The lsmean numbers of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 28.41 vs 16.48 (6.60, 17.25) and 25.00 vs 15.25 (0.58, 18.93) for left- and right-hand, respectively. CONCLUSIONS: Wind-up of second pain induced by noxious heat is sensitive to intervention by ketamine, which is known to block the NMDA receptor. These data infer that the wind-up phenomenon evoked by noxious heat involves the activation of NMDA receptors. This volunteer model of pain may have utility in the evaluation of agents that modulate their antinociceptive actions via NMDA mechanisms.

Acute Disease↗
PubMed1995

Pharmacokinetics of dextromethorphan and metabolites in humans: influence of the CYP2D6 phenotype and quinidine inhibition.

Dextromethorphan is primarily metabolized to dextrorphan by cytochrome P450 2D6 (CYP2D6), a genetically polymorphic enzyme in humans. Dextrorphan is an active metabolite that produces phencyclidine-like behavioral effects in animals and exhibits anticonvulsant and neuroprotective properties in a variety of experimental models. In these studies, we examined the effects of CYP2D6 phenotype and quinidine inhibition on the pharmacokinetics of dextromethorphan and its metabolites in humans. After a single oral dose of dextromethorphan HBr (30 mg), the major metabolites in the plasma of extensive metabolizers (N = 5) were conjugated dextrorphan and conjugated 3-hydroxymorphinan. Free dextrorphan concentrations were about 100-fold less than the conjugated dextrorphan, and dextromethorphan was not detectable. Pretreatment of these subjects with 100 mg of quinidine, a selective inhibitor of CYP2D6, significantly suppressed the formation of dextrorphan and elevated the concentrations of dextromethorphan (t1/2, 16.4 hours). In poor metabolizers (N = 4) given the same dose, dextromethorphan was the major component in the plasma with a t1/2 of 29.5 hours. Present at concentrations 5- to 10-fold less were conjugated dextrorphan and the other two metabolites. Urinary recovery studies indicated that the inhibition by quinidine was reversible and that the elimination of dextromethorphan primarily depends on CYP2D6 activity rather than renal elimination. These data demonstrated that the CYP2D6 phenotype and the concurrent administration of quinidine significantly affect the disposition of dextromethorphan and the formation of the active metabolite dextrorphan and are important factors to be considered in studies of the pharmacologic and behavioral effects of dextromethorphan.

Adult↗
PubMed1986

Pharmacogenetics of dextromethorphan O-demethylation in man.

The metabolism of dextromethorphan has been investigated from the aspect of genetically determined intersubject differences of oxidative drug metabolism in man. For this purpose, the urinary elimination of dextromethorphan and dextrorphan, which is the major O-demethylated metabolite in urine, has been studied in selected drug hydroxylation phenotypes. Dextromethorphan O-demethylation co-segregates with polymorphic debrisoquine hydroxylation, whereas no such co-segregation exists with the independently controlled mephenytoin polymorphism in man. The urinary dextromethorphan over dextrorphan metabolic ratio was validated for linearity of O-demethylation vs dose administered, and for varying urine collection intervals at different urinary pH values. A 94% repeatability of the dextromethorphan metabolic ratio could be established in extensive and poor metabolizer phenotypes. In a preliminary study, different rates of N-, O- and N,O- demethylation of dextromethorphan to yield D-methoxymorphinane, dextrorphan and D-hydroxymorphinane, respectively, were found in extensive- (Sprague-Dawley) and poor-metabolizer (female dark Agouti) rat strains. The observed interphenotype differences in man and the interstrain variations in an experimental animal model indicate that dextromethorphan O-demethylation is catalysed by the debrisoquine-type cytochrome P-450 isozyme. Therefore, the common genetic control of debrisoquine and dextromethorphan metabolism indicates that dextromethorphan might be used as a safe and innocuous substitute for debrisoquine in future routine phenotyping in the field of human pharmacogenetics of oxidative drug metabolism.

Adult↗
PubMed1994

Dextromethorphan metabolism in rat: interstrain differences and the fate of individually administered oxidative metabolites.

1. Dextromethorphan undergoes O- and N-demethylation, with the resultant metabolites being further N- and O-demethylated respectively to 3-hydroxymorphinan. The polymorphically expressed O-demethylation reaction is catalysed by P4502D1 in the Sprague-Dawley (SD) rat. The Dark-Agouti (DA) rat lacks this enzyme. 2. The aims were: (1) to determine if there were strain differences also in the Hooded Wistar (HW) and Albino Wistar (AW) rats with respect to the four demethylation reactions after dextromethorphan 20 mg/kg intraperitoneally; (2) to investigate the inhibition of the demethylation reactions by quinine and quinidine (each 40 mg/kg i.p.) in the above strains; and (3) to investigate the fate of separately administered metabolites (5 mg/kg i.p.) of dextromethorphan in the SD strain. 3. The total recovery of dextromethorphan and metabolites in the four strains ranged from 38 to 64% of the dose. The O-demethylation ratios (expressed as the ratio of urinary total dextrorphan divided by dextromethorphan) in the AW and DA strains were similar but less than in the SD/HW strains; the N-demethylation ratios (expressed as the ratio of urinary total 3-hydroxymorphinan plus 3-methoxymorphinan divided by dextromethorphan) in the DA and SD strains were similar but greater than in the AW and HW strains. Quinine and quinidine significantly reduced the O-demethylation ratio in the SD and DA rat strains, and the N-demethylation ratio in the SD strain. 4. In the SD rat the major metabolic route was via O-demethylation to dextrorphan. The source of 3-hydroxymorphinan is primarily from N-demethylation of dextromethorphan to 3-methoxymorphinan and its subsequent O-demethylation to 3-hydroxymorphinan. The O-demethylation metabolic ratio for dextromethorphan should be calculated as the quotient of urinary total dextrorphan divided by dextromethorphan.

Animals↗
PubMed2006

Dextromethorphan abuse in adolescence: an increasing trend: 1999-2004.

OBJECTIVES: To analyze the trend of dextromethorphan abuse in California and to compare these findings with national trends. DESIGN: A 6-year retrospective review. SETTING: California Poison Control System (CPCS), American Association of Poison Control Centers (AAPCC), and Drug Abuse Warning Network (DAWN) databases from January 1, 1999, to December 31, 2004. PARTICIPANTS: All dextromethorphan abuse cases reported to the CPCS, AAPCC, and DAWN. The main exposures of dextromethorphan abuse cases included date of exposure, age, acute vs long-term use, coingestants, product formulation, and clinical outcome. Main Outcome Measure The annual proportion of dextromethorphan abuse cases among all exposures reported to the CPCS, AAPCC, and DAWN databases. RESULTS: A total of 1382 CPCS cases were included in the study. A 10-fold increase in CPCS dextromethorphan abuse cases from 1999 (0.23 cases per 1000 calls) to 2004 (2.15 cases per 1000 calls) (odds ratio, 1.48; 95% confidence interval, 1.43-1.54) was identified. Of all CPCS dextromethorphan abuse cases, 74.5% were aged 9 to 17 years; the frequency of cases among this age group increased more than 15-fold during the study (from 0.11 to 1.68 cases per 1000 calls). Similar trends were seen in the AAPCC and DAWN databases. The highest frequency of dextromethorphan abuse occurred among adolescents aged 15 and 16 years. The most commonly abused product was Coricidin HBP Cough & Cold Tablets. CONCLUSIONS: Our study revealed an increasing trend of dextromethorphan abuse cases reported to the CPCS that is paralleled nationally as reported to the AAPCC and DAWN. This increase was most evident in the adolescent population.

Adolescent↗
PubMed2005

Dextromethorphan metabolic phenotyping in an Iranian population.

OBJECTIVE: CYP2D6 polymorphism of drug metabolism represents an important source of interindividual and interethnic variation in drug response. Since this polymorphism has not been studied in an Iranian population, the present study was undertaken. METHODS: Two hundred healthy unrelated Iranian subjects participated in this study. Phenotyping was based on high-performance liquid chromatography determination of the dextromethorphan/total dextrorphan molar ratios as metabolic ratios (MRs) in plasma samples collected at 3 h after oral administration of 30 mg dextromethorphan hydrobromide. Since the dextromethorphan detection limit of 5 ng/ml achieved in the simultaneous assay for dextromethorphan and its metabolites was not adequate to identify intermediate metabolizers (IMs), 80 of 200 samples selected randomly were also assayed using a modified, more sensitive procedure with a dextromethorphan detection limit of 1 ng/ml. RESULTS: Poor and extensive metabolizers (EMs) could be identified distinctly. A 520-fold interindividual variation in dextromethorphan MRs was observed in this study. In contrast to undetectable dextrorphan and hydroxymorphinan concentrations, clearly determinable dextromethorphan concentrations higher than 10 ng/ml were observed in plasma samples of poor metabolizers (PMs). Considering the antimode of 0.3, five (2.5%, 95% confidence interval of 0.34-4.66) volunteers were identified as PMs. Using the more sensitive method, dextromethorphan was quantified in 4 (one PM) of 80 samples. Excluding the PM, a Shapiro-Wilk test indicated a non-normal distribution of MRs (P < 0.01) in the latter population. CONCLUSIONS: From this study it can be concluded that the frequency of PMs in an Iranian population is 2.5% (95% confidence interval of 0.34-4.66). IMs could be identified using dextromethorphan plasma assays with detection limits of at least 1 ng/ml. However, the phenotype-genotype relationships in this respect remain to be established.

Adult↗
PubMed1993

Differences in anticonvulsant potency and adverse effects between dextromethorphan and dextrorphan in amygdala-kindled and non-kindled rats.

The anticonvulsant and adverse effects of dextromethorphan, a non-opioid antitussive, and its metabolite dextrorphan were examined in amygdala-kindled rats. Both drugs have repeatedly been proposed to be functional non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, but they also exert effects distinct from antagonism at NMDA receptors, such as blockade of voltage-gated calcium channels and sigma-site mediated actions. Since recent data have demonstrated that kindled rats are more susceptible to the adverse effects of NMDA receptor antagonists than non-kindled rats, the time course, characteristics and severity of adverse effects of dextromethorphan and dextrorphan were also determined in non-kindled animals. Dextromethorphan dose dependently increased the focal seizure threshold (i.e. the threshold for induction of afterdischarges recorded from the amygdala) in fully kindled rats. This anticonvulsant effect was found at relatively low doses (7.5-15 mg/kg i.p.) which were almost free of any adverse effects. At higher doses, dextromethorphan induced motor impairment and seizures, but no phenyclidine (PCP)-like adverse effects, such as hyperlocomotion or stereotypies. In contrast, such adverse effects were seen after dextrorphan, although only infrequently. Dextrorphan was less potent in inducing anticonvulsant but more potent in inducing motor impairing effects than dextromethorphan in kindled rats. In non-kindled rats, the motor impairment induced by dextrorphan was significantly less severe than in kindled rats, whereas no marked differences between kindled and non-kindled rats were found for dextromethorphan. The data indicate that dextromethorphan and dextrorphan differ in their mechanisms of action. Only dextrorphan exerts effects which are characteristic for NMDA receptor antagonism, whereas the potent anticonvulsant effect of dextromethorphan in presumably unrelated to the NMDA receptor complex.

Amygdala↗
PubMed2006

Dextromethorphan, 3-methoxymorphinan, and dextrorphan have local anaesthetic effect on sciatic nerve blockade in rats.

Dextromethorphan has been used as an antitussive for more than 40 years and is considered a drug with a good margin of safety. The aim of the study was to evaluate whether dextromethorphan and its metabolites--3-methoxymorphinan and dextrorphan--had local anaesthetic effects. Using a method of sciatic nerve blockade in rats, the potencies and durations of actions of dextromethorphan and its metabolites on sciatic nerve blockades of motor function, proprioception, and nociception were evaluated. Lidocaine was used as control. We found that dextromethorphan and its metabolites produced dose-related local anaesthetic effects on sciatic nerve blockades of motor function, proprioception, and nociception. The ranks of potencies were lidocaine>dextromethorphan>3-methoxymorphinan>dextrorphan (P<0.01 for each comparison). Under an equi-potent basis, dextrorphan and 3-methoxymorphinan had durations of actions longer than that of lidocaine (P<0.05 for each comparison). Co-administration of dextromethorphan or its metabolites with lidocaine produced an additive effect on sciatic nerve blockades. In conclusion, dextromethorphan and its metabolites - 3-methoxymorphinan and dextrorphan- had a local anaesthetic effect on sciatic nerve blockades of motor function, proprioception and nociception with durations of actions longer than that of lidocaine. Co-administration of dextromethorphan and its metabolites produced an additive effect on sciatic nerve blockades.

Anesthetics, Local↗
PubMed1997

Dextromethorphan reduces intravenous cocaine self-administration in the rat.

Dextromethorphan is a widely used antitussive agent with non-competitive antagonistic effects at the excitatory amino acid receptors of the NMDA type. Since excitatory amino acid neurotransmission has been implicated in cocaine dependence, the aim of the present study was to evaluate the effects of acute systemic administration of dextromethorphan in rats trained to self-administer cocaine intravenously. The experiments were designed to evaluate the effects of dextromethorphan on responding for cocaine and cocaine reward magnitude. The hypothesis was that dextromethorphan could attenuate specific aspects of cocaine-seeking behavior thus providing a preclinical rationale for its clinical use. The results reported reveal that acute pretreatment with dextromethorphan (10-50 mg/kg i.p.) significantly reduced cocaine self-administration in rats self-administering the drug intravenously in a simple continuous reinforcement schedule. In addition, acute pretreatment with an effective dose of dextromethorphan (25 mg/kg) decreased cocaine self-administration in rats tested at various doses of cocaine (0.12-0.5 mg/injection). Finally, dextromethorphan (25 mg/kg) also reduced the absolute reward magnitude of cocaine as measured by responding for cocaine in a progressive ratio schedule. These results encourage further experimental and clinical studies to evaluate the potential use of dextromethorphan during various phases of the natural history of cocaine dependence in humans.

Animals↗
PubMed2002

A sensitive LC-MS/MS assay for the determination of dextromethorphan and metabolites in human urine--application for drug interaction studies assessing potential CYP3A and CYP2D6 inhibition.

The commonly used antitussive dextromethorphan can be used to simultaneously assess potential cytochrome P450 3A (CYP3A) and CYP2D6 inhibition during drug development. The metabolism of dextromethorphan to dextrorphan and subsequently to 3-hydroxymorphinan are via the 2D6 pathway, while the metabolism of dextromethorphan to 3-methoxymorphinan is via the 3A pathway. A sensitive and specific LC-MS/MS assay has been developed to determine the human urine concentrations of dextromethorphan and three metabolites (dextrorphan, 3-methoxymorphinan and 3-hydroxymorphinan) in support of drug interaction studies. Urine samples (0.5 ml), after enzymatic hydrolysis of the conjugates and containing 3-ethylmorphine as an internal standard, were extracted with chloroform under basic conditions. Following concentration and reconstitution, the samples were analyzed by LC-MS/MS. The assay was linear over the range of 5.00-500 ng/ml for dextromethorphan and 3-methoxymorphinan; and 200-3000 ng/ml for dextrorphan and 3-hydroxymorphinan using a Perkin-Elmer Sciex triple quadrupole mass spectrometer (API 300). The intra- and inter-day relative standard deviation (RSD) across three validation runs over the entire concentration range for all analytes was less than 15%. Accuracy determined at three or four concentrations (9.00, 200, and 400 ng/ml for dextromethorphan and 3-methoxymorphinan; 250, 400, 1300 and 2500 ng/ml for dextrorphan and 3-hydroxymorphinan) ranged between 96.3 and 113.8%. The stability of analytes in urine was demonstrated for 9 months at -20 degrees C, 24 h under ambient conditions and for up to three freeze/thaw cycles. The method described herein is suitable for the rapid and efficient measurement of dextromethorphan and different metabolites to estimate potential CYP3A inhibition by drug candidates and for screening of extensive and poor metabolizers of CYP2D6 in the heterogeneous population. The method has subsequently been validated on a Sciex API 3000 with lower limit of quantitation; 1.00 ng/ml for dextromethorphan and 3-methoxymorphinan; 60.0 ng/ml for dextrorphan and 100 ng/ml for 3-hydroxymorphinan.

Aryl Hydrocarbon Hydroxylases↗
PubMed1992

Dextromethorphan: enhancing its systemic availability by way of low-dose quinidine-mediated inhibition of cytochrome P4502D6.

There has been a substantial amount of interest in the anticonvulsant and neuroprotective actions of dextromethorphan. Its therapeutic efficacy, however, is limited by its extensive first-pass elimination by way of the cytochrome P4502D6 enzyme in humans. The purpose of this research was to determine whether quinidine (a selective inhibitor of cytochrome P4502D6) could improve dextromethorphan systemic delivery in patients with amyotrophic lateral sclerosis (a neurodegenerative disease). In the absence of quinidine, 60 mg dextromethorphan every 12 hours resulted in plasma concentrations of only 12 +/- 13 ng/ml (range, less than 5 to 40 ng/ml; n = 7). The same dose of dextromethorphan in the presence of 75 mg quinidine every 12 hours resulted in dextromethorphan plasma concentrations of 241 +/- 94 ng/ml (range, 157 to 402 ng/ml; n = 5). The achievement of higher dextromethorphan plasma concentrations was also associated with an increased occurrence of adverse effects in some patients. Based on the brain/plasma ratio for dextromethorphan in rats, it is estimated that brain dextromethorphan concentrations of 1.0 to 10 micrograms/gm may be attainable in humans by inhibition of cytochrome P4502D6 activity with quinidine.

Adult↗
PubMed1993

Neuroprotection following focal cerebral ischaemia with the NMDA antagonist dextromethorphan, has a favourable dose response profile.

Although N-methyl-D-Aspartate (NMDA) antagonists protect against focal cerebral ischaemia, there is concern that the high doses necessary for neuroprotection may cause unacceptable adverse effects. We studied the dose response characteristics of the clinically available NMDA antagonist dextromethorphan in a rabbit model of transient focal ischaemia. Thirty-three anaesthetized rabbits underwent occlusion of the left internal carotid and anterior cerebral arteries for 1 h followed by 4.5 h of reperfusion. One hour after the onset of ischaemia, they were treated with an i.v. infusion of varying doses of dextromethorphan or normal saline. Seventeen additional unanaesthetized, nonischaemic rabbits received similar infusions of dextromethorphan to correlate brain with blood levels and to evaluate adverse effects. Rabbits with plasma dextromethorphan levels 500-1500 ng ml-1 had a 64% reduction in ischaemic neuronal damage (p < 0.05); those with levels > 1500 ng ml-1 showed 92% attenuation of neuronal damage and 65% decrease in ischaemic oedema (p < 0.01). Drug levels suggest that dextromethorphan's neuroprotection is not mediated by its active metabolite dextrorphan. Unanaesthetized rabbits with plasma levels > 2500 ng ml-1 demonstrated severe gait ataxia. These results demonstrate that systemic treatment with dextromethorphan after 1 h of focal ischaemia can significantly protect against cerebral damage if adequate plasma and brain levels are achieved. Dextromethorphan was concentrated 7-30 x in brain compared with plasma, and brain levels were highly correlated with plasma levels (r = 0.89). Neuroprotective doses of dextromethorphan were tolerated with only transient side effects.

Animals↗
PubMed1993

High-performance liquid chromatography determination of dextromethorphan and dextrorphan for oxidation phenotyping by fluorescence and ultraviolet detection.

To establish the usefulness of fluorescence detection to quantify urinary concentrations of dextromethorphan and dextrorphan for oxidation phenotyping, we determined the molar concentration ratio of dextromethorphan to dextrorphan in 38 subjects by UV and fluorescence detection. Dextromethorphan and dextrorphan concentrations were quantified after overnight hydrolysis of urine samples and organic solvent extraction with heptane and butanol. The compounds were separated by high-performance liquid chromatography using a phenyl column and a mobile phase consisting of acetonitrile and an aqueous mixture of 0.01 M heptane sulfonic acid and 0.01 M phosphate buffer. The eluents were detected in series by a UV detector (280 nm) and fluorescence detector (excitation 280 nm and emission 310 nm). The dextromethorphan to dextrorphan molar concentration ratio by UV and fluorescence detection was highly correlated (r = 0.997) and not statistically different (p = 0.1036). However, increased sensitivity with fluorescence detection enabled detection of lower dextromethorphan and dextrorphan concentrations when compared with UV detection. Fluorescence detection was able to detect dextromethorphan as low as 0.02 microgram/ml, which may be helpful in phenotyping individuals with extremely rapid metabolism of dextromethorphan. Fluorescence detection also produced chromatograms with significantly less interference and allows a more accurate quantitation of dextromethorphan and dextrorphan concentrations.

Chromatography, High Pressure Liquid↗