Concentrations Of Dextromethorphan Research Articles

A clinical pharmacokinetic drug-drug interaction study between dextromethorphan and emvododstat, a potent anti-SARS-CoV-2 dihydroorotate dehydrogenase inhibitor

PurposeA therapeutic agent that targets both viral replication and the hyper-reactive immune response would offer a highly desirable treatment for severe acute respiratory syndrome corona virus 2 (SARS-CoV-2, coronavirus disease 2019, COVID-19) management. Emvododstat (PTC299; 4-chlorophenyl 6-chloro-1-[4-methoxyphenyl]-1,3, 4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate) was found to be a potent inhibitor of immunomodulatory and inflammation-related processes by inhibition of dihydroorotate dehydrogenase to reduce the severity of SARS-CoV-2 infections This drug interaction study was performed to determine if emvododstat was an inhibitor of CYP2D6.MethodsPotential drug-drug interactions between emvododstat and a CYP2D6 probe substrate (dextromethorphan) were investigated by measuring plasma dextromethorphan and metabolite (dextrorphan) concentrations before and after emvododstat administration. On day 1, 18 healthy subjects received an oral dose of 30 mg dextromethorphan followed by a 4-day washout period. On day 5, subjects received an oral dose of 250 mg emvododstat with food. Two hours later, 30 mg dextromethorphan was administered.ResultsWhen given with emvododstat, plasma dextromethorphan concentrations increased substantially, while metabolite levels (dextrorphan) remained essentially the same. Maximum plasma dextromethorphan concentration (Cmax) increased from 2006 to 5847 pg/mL. Dextromethorphan exposure (AUC) increased from 18,829 to 157,400 h·pg/mL for AUC0-last and from 21,585 to 362,107 h·pg/mL for AUC0-inf following administration of emvododstat. When dextromethorphan parameters were compared before and after emvododstat, least squares mean ratios (90% confidence interval) were found to be 2.9 (2.2, 3.8), 8.4 (6.1, 11.5), and 14.9 (10.0, 22.1) for Cmax, AUC0-last, and AUC0-inf, respectively.ConclusionEmvododstat appears to be a strong CYP2D6 inhibitor. No drug-related treatment emergent adverse effects (TEAEs) were considered to be severe or serious.Trial registrationEudraCT 2021-004626-29, 11 May 2021.

Infant Dextromethorphan and Dextrorphan Exposure via Breast Milk From Mothers Who Are CYP2D6 Extensive Metabolizers.

The risk of infant exposure to dextromethorphan (DM) and its active metabolite, dextrorphan (DX), through breast milk has not been evaluated. In this study, bound and unbound DM and DX concentrations in breast milk and plasma at 2hours post-dose were measured in 20 lactating women (n=20) following a single 30 mg oral dose of DM. The DM and DX concentrations in breast milk were positively correlated with their respective plasma concentrations. The breast milk-to-plasma (M/P) ratios of 1.0 and 1.6 and the unbound M/P ratios of 1.1 and 2.0 for DM and DX, respectively, suggested that DM and DX are extensively distributed into breast milk. The infant exposure following a single dose of 30 mg DM was estimated using breast milk concentrations of 0.33±0.32 and 1.8±1.0μg/kg/day for DM and DX, respectively. The steady-state infant exposure was estimated using the M/P ratios and previously reported area under the concentration-time curve (AUC) of DM and DX following repeated dosing of DM 60mg orally, twice daily, to be 0.64±0.22 and 1.23±0.38μg/kg/day, respectively. Based on these estimated infant doses, the relative infant doses (RIDs) were estimated to be <1%, suggesting the infant is only exposed to a minor fraction of adult dose through breast milk; however, one nursing infant developed an erythematous rash during this study, which warrants additional research to fully elucidate the risks of infant exposure to DM and DX through breast milk.

Deuterated dextromethorphan/quinidine for agitation in Alzheimer's disease.

Deuterated dextromethorphan/quinidine for agitation in Alzheimer's disease.

Dextromethorphan Abuse Among Opioid-Dependent Patients.

Among opioid-dependent patients on maintenance therapy, concomitant drug abuse is a serious problem. Dextromethorphan, an over-the-counter antitussive agent that can be purchased without prescription, is a drug with a high potential for misuse, especially when consumed in high doses.The objective of this study was to investigate possible abuse of dextromethorphan among substituted opioid-dependent patients and comparison of subjective and objective findings.Due to its ability to increase serotonin levels, opioid-dependent patients may be particularly susceptible to dextromethorphan misuse. Dextromethorphan misuse may have side effects, including psychiatric symptoms and serotonin syndrome, and may induce assault, suicide, or homicide. A total of 104 opioid-dependent patients in maintenance treatment were included in this cross-sectional study conducted in the outpatient department of the Psychiatric Hospital, University of Zurich. Study participants were divided into 2 groups based on laboratory results: dextromethorphan abusers (n = 12) and nonabusers (n = 92). The objective use and concentrations of dextromethorphan was detected using 3-month hair toxicology analysis.Statistical analysis was performed by using χ test, Student t test, Mann-Whitney U test, and Barnard exact test. Dextromethorphan was abused by 12 (11.5%) patients, 11 (91.7%) of whom did not report concomitant abuse of dextromethorphan but were identified through hair analysis. In general, there were significant differences among patients abusing dextromethorphan compared with nondextromethorphan consumers in terms of trauma due to sexual maltreatment/violence, multiple traumas, or harmful use of hallucinogenic drugs. Further studies are necessary to examine dextromethorphan and its impact on patients with psychiatric comorbidities and psychiatric medication. According to literature, there is a significant drug interaction risk due to the impact of dextromethorphan misuse on serotonin syndrome and psychiatric symptoms.1-3 We recommend active inquiry into and testing for concomitant drug abuse among substituted opioid-dependent patients to reduce the risk of drug interactions and side effects in this especially vulnerable group of patients.

Simultaneous Determination of Active Ingredients in Multicomponent Common Over the Counter Tablets in the Present of Parabens and 4-Aminophenol by HPLC

A new selective reverse-phase high-performance liquid chromatography method with an attitude of practical use in pharmaceutical laboratories for simultaneous determination of Ascorbic acid, Acetaminophen, phenylephrine, Caffeine, Pamabrom, Guaifenesin, Dextromethorphan, Pyrilamine, Chlorpheniramine maleate, Ibuprofen in the presence of Methyl, Ethyl, Butyl Parabens as preservatives has been developed and validated. These active pharmaceutical ingredients widely used in a variety of cough and cold medicines. The separation was carried out on an Atlantis dC18 column including 4.6 mm inner diameter, 150 mm length and particle size of 3 μm, using a mobile phase which consisted of an ion-pairing agent (sodium salt of heptane sulphonic acid) as a buffer solution mixed with acetonitrile as an organic modifier at a flow rate of 1 mL min−1 on a gradient system. The investigation was carried out on wavelength program detection to quantify the very low concentration of Dextromethorphan and Chlorpheniramine and high concentration of Acetaminophen, Guaifenesin, Ibuprofen, Ascorbic Acid at the wavelengths of 290 and 215 nm. The temperature was maintained at 40 °C. The method was shown to be linear (R2 > 0.996), accurate (recoveries 97.77–103.94%), precise (RSD ≤ 1.0%), sensitive, specific, simple, fast and robust. The proposed reverse phase-liquid chromatography method was successfully applied to the routine analysis of the Over-The-Counter tablets containing these active pharmaceutical ingredients without any interference with excipients and parabens and 4-aminophenol.

Central Sensitization, N-methyl-D-aspartate Receptors, and Human Experimental Pain Models: Bridging the Gap between Target Discovery and Drug Development.

Central Sensitization, N-methyl-D-aspartate Receptors, and Human Experimental Pain Models: Bridging the Gap between Target Discovery and Drug Development.

Gas chromatography tandem mass spectrometry for the screening of adulterants in seized captagon™ tablets

Background: Amphetamine type stimulants (ATS) are the second most popular illegal drugs used worldwide, after cannabis. The production of ATS has increased across the world, including the Middle East. Fenethylline (Captagon™), amphetamine derivative, sold as a street drug usually contains several adulterants and diluents. In Saudi Arabia, like other countries, samples of illicit ATS are submitted to laboratories to test for the adulterated compounds.Objective: The objective of the proposed study was to apply gas chromatography/mass spectrometry (GC/MS) for fenethylline profiling of seized samples collected from the Saudi market (n = 55).Methodology: The GC/MS analysis was performed on a general purpose column (30 m × 0.25 mm i.d) coated with 0.25 µm cross bond, 5% diphenyl dimethyl polysiloxane (Rtx-5MS). The mass was operated in the electron impact mode.Results and discussion: Analyzed samples gave positive results for amphetamine in the concentration range between 1.35% and 37.32% of the powder, caffeine in the range between 22.74 and 44.92%, in addition to different concentrations of levoglucosenone, theophylline, D-allose, lidocaine, methamphetamine, dextromethorphan, and other adulterants. Finally, the presence of other substances in fenethylline street samples could result in intoxication. This significantly contributes to the potential risk of drug addiction among public.

Evaluating the effect of Ganoderma lucidum polysaccharides on five cytochrome P450 isozymes with cocktail probe drugs in rats by LC–MS/MS

Ganoderma lucidum polysaccharides (GLPs) are commonly used as health-promoting medicine and dietary supplement due to the positive effects in immune modulation, antitumor and antioxidant activities. However, whether GLPs executes other uncharacterized effects is largely unclear. The rats were pre-primed with GLPs and then administrated with canonical “cocktail probes” of cytochrome P450 (CYP450) isozymes including caffeine, tolbutamide, dextromethorphan, omeprazole, and midazolam. The plasma concentrations of probes at each indicated time point were simultaneously detected using the designed high-performance liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. The results suggested that GLPs could increase the accumulated levels of caffeine, tolbutamide and midazolam in plasma as compared to control group. Besides, GLPs reduced the concentration of dextromethorphan in blood at high dose, while elevated it at low dose. GLPs could inhibit the activities of CYP1A2, and CYP3A4, additionally; GLPs at low dose suppressed the activity of CYP2D6, which demonstrated that drugs co-administrated with GLPs might require strictly evaluating the dose relation.

Ultralow doses of dextromethorphan protect mice from endotoxin-induced sepsis-like hepatotoxicity

Dextromethorphan, a wildly used over-the-counter antitussive drug, is reported to have anti-inflammatory effects. Previously, we and others have demonstrated that dextromethorphan at micromolar doses displays potent hepatoprotective effects and enhances mice survival in a sepsis model. Moreover, we also observed potent anti-inflammatory and neuroprotective effects of subpicomolar concentrations of dextromethorphan in rodent primary neuron-glial cultures. The purpose of this study was to provide a proof of principle that ultralow dose dextromethorphan displays anti-inflammatory and cytoprotective effects in animal studies. Here, we report that subpico- and micromolar doses of dextromethorphan showed comparable efficacy in protecting mice from lipopolysaccharide/d-galactosamine (LPS/GalN)-induced hepatotoxicity and mortality. Mice were given injections of dextromethorphan from 30 min before and 2, 4 h after an injection of LPS/GalN (20 μg/600 mg/kg). Our results showed that dextromethorphan at subpicomolar doses promoted survival rate in LPS/GalN-injected mice. Ultralow dose dextromethorphan also significantly reduced serum alanine aminotransferase activity, TNF-α level and liver cell damage of endotoxemia mice. Mechanistic studies using primary liver Kupffer cell cultures revealed that subpicomolar concentrations of dextromethorphan reduced the NADPH oxidase-generated superoxide free radicals from Kupffer cells, which in turn reduced the elevation of its downstream reactive oxygen species (iROS) to relieve the oxidative stress and decreased TNF-α production in Kupffer cells. Taken together, these findings suggest a novel therapeutic concept of using ultralow doses of dextromethorphan for the intervention of sepsis or septic shock.

Kinetics of dextromethorphan-O-demethylase activity and distribution of CYP2D in four commonly-used subcellular fractions of rat brain

The purpose of this study was to compare the enzymatic kinetics and distribution of cytochrome P450 2D (CYP2D) among different rat brain subcellular fractions.Rat brains were used to prepare total membrane, crude mitochondrial, purified mitochondrial, and microsomal fractions, in addition to total homogenate. Michaelis–Menten kinetics of the brain CYP2D activity was estimated based on the conversion of dextromethorphan (DXM) to dextrorphan using UPLC-MS/MS. Protein levels of CYP2D and subcellular markers were determined by Western blot.Microsomal CYP2D exhibited high affinity and low capacity, compared with the mitochondrial CYP2D that had a much lower (∼50-fold) affinity but a higher (∼six-fold) capacity. The apparent CYP2D affinity and capacity of the crude mitochondria were in between those of the microsomes and purified mitochondria. Additionally, the CYP2D activity in the whole homogenate was much higher than that in the total membranes at higher DXM concentrations. A CYP2D immune-reactive band in the brain mitochondria appeared at a lower MW but had a much higher intensity than that in the microsomes.Mitochondrial brain CYP2D has a much higher capacity than its microsomal counterpart. Additionally, brain homogenate is more representative of the overall CYP2D activity than the widely-used total membrane fraction.

UPLC-MS/MS analysis of dextromethorphan-O-demethylation kinetics in rat brain microsomes

Formation of dextrorphan (DXT) from dextromethorphan (DXM) has been widely used to assess cytochrome P450 2D (CYP2D) activity. Additionally, the kinetics of CYP2D activity have been well characterized in the liver microsomes. However, studies in brain microsomes are limited due to the lower microsomal content and abundance of CYP2D in the brain relative to the liver. In the present study, we developed a micro-scale enzymatic incubation method, coupled with a sensitive UPLC-MS/MS assay for the quantitation of the rate of DXT formation from DXM in brain microsomes. Rat brain microsomes were incubated with different concentrations of DXM for various times. The reaction was stopped, and the proteins were precipitated by the addition of acetonitrile, containing internal standard (d3-DXT). After centrifugation, supernatant (2 μL) was injected onto a UPLC, C18 column with gradient elution. Analytes were quantitated using triple-quadrupole MS/MS with electrospray ionization in positive ion mode. The assay, which was validated for accuracy and precision in the linear range of 0.25 nM to 100 nM DXT, has a lower limit of quantitation of 0.125 fmol on the column. Using our optimized incubation and quantitation methods, we were able to reduce the incubation volume (25 μL), microsomal protein amount (5 μg), and incubation time (20 min), compared with reported methods. The method was successfully applied to estimation of the Michaelis-Menten (MM) kinetic parameters of dextromethorphan-O-demethylase activity in the rat brain microsomes (mean ± SD, n = 4), which showed a maximum velocity of 2.24 ± 0.42 pmol/min/mg and a MM constant of 282 ± 62 μM. It is concluded that by requiring far less biological material and time, our method represents a significant improvement over the existing techniques for investigation of CYP2D activity in rat brain microsomes.

Evaluation of CYP2D6 phenotype in the Yoruba Nigerian population

ABSTRACTBackground: There is a lack of information on CYP2D6, a major metabolizing enzyme, in Africa ethnic nationalities. The objective was to determine CYP2D6 phenotype in Yoruba Nigerians using dextromethorphan (DEX).Method: A total of 89 healthy volunteers received 30 mg of DEX orally followed by blood and urine sample collection at 3-hour and over 8 h post-dose, respectively. DEX and dextrorphan (DOR) concentrations were determined using High Performance Liquid Chromatography (HPLC). The metabolic ratio (MR, DEX/DOR) were plotted for the phenotype determination.Results: The log MR that separated poor (PMs) from normal metabolizers (NMs) was 0.28 and 0.75 for urine and plasma, respectively. Two subjects (2.3%) identified as PMs had a mean MR of 17 and 3.2 in plasma and urine, significantly higher than that of NMs (p < .0001). A positive correlation between urine and plasma MR was noted.Conclusion: The prevalence of PMs in the Yoruba Nigerians was similar to that reported among blacks.

Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use.

Dextromethorphan (DM) has been used for more than 50years as an over-the-counter antitussive. Studies have revealed a complex pharmacology of DM with mechanisms beyond blockade of N-methyl-d-aspartate (NMDA) receptors and inhibition of glutamate excitotoxicity, likely contributing to its pharmacological activity and clinical potential. DM is rapidly metabolized to dextrorphan, which has hampered the exploration of DM therapy separate from its metabolites. Coadministration of DM with a low dose of quinidine inhibits DM metabolism, yields greater bioavailability and enables more specific testing of the therapeutic properties of DM apart from its metabolites. The development of the drug combination DM hydrobromide and quinidine sulfate (DM/Q), with subsequent approval by the US Food and Drug Administration for pseudobulbar affect, led to renewed interest in understanding DM pharmacology. This review summarizes the interactions of DM with brain receptors and transporters and also considers its metabolic and pharmacokinetic properties. To assess the potential clinical relevance of these interactions, we provide an analysis comparing DM activity from in vitro functional assays with the estimated free drug DM concentrations in the brain following oral DM/Q administration. The findings suggest that DM/Q likely inhibits serotonin and norepinephrine reuptake and also blocks NMDA receptors with rapid kinetics. Use of DM/Q may also antagonize nicotinic acetylcholine receptors, particularly those composed of α3β4 subunits, and cause agonist activity at sigma-1 receptors.

Application of Modified Carbon Quantum Dots/Multiwall Carbon Nanotubes/Pencil Graphite Electrode for Electrochemical Determination of Dextromethorphan

In this paper, highly amino-functionalized fluorescent carbon quantum dots (CDs) were fabricated by hydrothermal carbonization of chitosan at mild temperature. Multiwall carbon nanotubes (MWCNTs) and CD were used in the preparation of working electrode. This sensor was based on a poly (diallyl-dimethyl ammonium chloride)/MWCNT/CD modified pencil graphite electrode for monitoring dextromethorphan (DXM) oxidation signals. The morphology and features of the various modifiers that were formed at the electrode surface investigated by field emission scanning electron microscopy. The modified sensor displayed excellent selectivity toward DXM. Electrochemical methods, such as cyclic voltammetry and differential pulse voltammetry were used for the characterization of sensor. Under the optimal experimental conditions, the current response and the concentration of DXM exhibited a linear relationship in the range of 2–600 $\mu \text{M}$ with the detection limit of 0.2 $\mu \text{M}$ . This sensor was successfully applied to determine DXM in the cough syrups, human urine, and plasma samples.

The Psychostimulant Khat (Catha edulis) Inhibits CYP2D6 Enzyme Activity in Humans.

The use of khat (Catha edulis) while on medication may alter treatment outcome. In particular, the influence of khat on the metabolic activities of drug-metabolizing enzymes is not known. We performed a comparative 1-way crossover study to evaluate the effect of khat on cytochrome P450 (CYP)2D6 and CYP3A4 enzyme activity. After 1 week of khat abstinence, baseline CYP2D6 and CYP3A4 metabolic activities were determined in 40 Ethiopian male volunteers using 30 mg dextromethorphan (DM) as a probe drug and then repeated after 1 week of daily use of 400 g fresh khat leaves. Urinary concentrations of cathinone and cathine were determined to monitor the subjects' compliance to the study protocol. Genotyping for CYP2D6*3 and CYP2D6*4 was done. Plasma DM, dextrorphan and 3-methoxymorphinan concentrations were quantified. CYP2D6 and CYP3A4 enzyme activities were assessed by comparing plasma log DM/dextrorphan and log DM/methoxymorphinan metabolic ratio (MR) respectively in the presence and absence of khat. Cytochrome 2D6 MR was significantly increased from baseline by concurrent khat use (paired t test, P = 0.003; geometric mean ratio, 1.38; 95% confidence interval [95% CI], 1.12-1.53). Moreover, the inhibition of CYP2D6 activity by khat was more pronounced in CYP2D6*1/*1 compared with CYP2D6*1/*4 genotypes (P = 0.01). A marginal inhibition of CYP3A4 activity in the presence of khat was observed (P = 0.24). The mean percentage increase of CYP2D6 and CYP3A4 MR from baseline by khat use was 46% (95% CI, 20-72) and 31% (95% CI, 8-54), respectively. This is the first report linking khat use with significant inhibition of CYP2D6 metabolic activity in humans.

Deaths due to abuse of dextromethorphan sold over-the-counter in Pakistan

Dextromethorphan is the most commonly used over-the-counter anti-tussive and expectorant medicine at therapeutic doses. Due to easy availability, euphoric high and hallucinogenic effects at larger doses, dextromethorphan popularity amongst the drug abusers is growing day by day. It is often mixed with alcohol, opiates, cannabinoids or other drugs of abuse for recreational purposes despite their lethal synergistic effects. More than 50 deaths were reported the first time in Pakistan after consuming cough syrups containing dextromethorphan, manufactured by two local pharmaceutical industries. All deceased had the history of drug abuse. We report the deaths of nineteen males, ages ranged from 17 to 45years, in two major cities of Pakistan who purposefully ingested large doses of dextromethorphan for recreational purposes and died as a result of direct toxic effects of the drug. Toxicological analysis revealed high levels of dextromethorphan ranging from 7.3 to 41.7mg/L in the peripheral blood, 4.2–92.6mg/kg in the liver and 9.9–349.6mg/L in the gastric content by high performance liquid chromatography. The dextromethorphan concentrations in all subjects significantly exceeded the therapeutic range and were consistent with concentrations reported in other cases of dextromethorphan abuse and toxicity. Besides dextromethorphan other drugs of abuse like cannabinoids, opiates, benzodiazepines, ethanol and chlorpheniramine were also detected. The cause of death was determined to be acute dextromethorphan intoxication with lethal synergistic effect of other co-ingested drugs of abuse. The deaths resulted in the prosecution of all individuals involved in manufacturing, distribution or sale of the cough syrup.

Dextromethorphan/quinidine: a review of its use in adults with pseudobulbar affect.

Fixed-dose dextromethorphan/quinidine capsules (Nuedexta(®)) utilize quinidine to inhibit the metabolism of dextromethorphan, enabling high plasma dextromethorphan concentrations to be reached without using a larger dose of the drug. The drug combination is the first treatment to be approved for pseudobulbar affect (PBA), a condition of contextually inappropriate/exaggerated emotional expression that often occurs in adults with neurological damage conditions, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, traumatic brain injury, Alzheimer's disease or Parkinson's disease. Dextromethorphan/quinidine at the recommended dosages of 20/10 or 30/10mg twice daily reduced the rate of PBA episodes and improved PBA severity in a 12-week, double-blind, placebo-controlled trial in adults with ALS or MS (STAR), with further improvements in the severity of the condition observed in a 12-week open-label extension phase. Dextromethorphan/quinidine 20/10mg twice daily also improved PBA secondary to dementia in a cohort of a 12-week noncomparative trial (PRISM II). The drug combination was generally well tolerated in these studies, with no particular safety or tolerability concerns. Although longer-term efficacy and tolerability data for dextromethorphan/quinidine 20/10 or 30/10mg twice daily would be beneficial, current evidence indicates that it is a useful option in the treatment of adults with PBA.

Involvement of sigma-1 receptors in the antidepressant-like effects of dextromethorphan.

Dextromethorphan is an antitussive with a high margin of safety that has been hypothesized to display rapid-acting antidepressant activity based on pharmacodynamic similarities to the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. In addition to binding to NMDA receptors, dextromethorphan binds to sigma-1 (σ1) receptors, which are believed to be protein targets for a potential new class of antidepressant medications. The purpose of this study was to determine whether dextromethorphan elicits antidepressant-like effects and the involvement of σ1 receptors in mediating its antidepressant-like actions. The antidepressant-like effects of dextromethorphan were assessed in male, Swiss Webster mice using the forced swim test. Next, σ1 receptor antagonists (BD1063 and BD1047) were evaluated in conjunction with dextromethorphan to determine the involvement of σ receptors in its antidepressant-like effects. Quinidine, a cytochrome P450 (CYP) 2D6 inhibitor, was also evaluated in conjunction with dextromethorphan to increase the bioavailability of dextromethorphan and reduce exposure to additional metabolites. Finally, saturation binding assays were performed to assess the manner in which dextromethorphan interacts at the σ1 receptor. Our results revealed dextromethorphan displays antidepressant-like effects in the forced swim test that can be attenuated by pretreatment with σ1 receptor antagonists, with BD1063 causing a shift to the right in the dextromethorphan dose response curve. Concomitant administration of quinidine potentiated the antidepressant-like effects of dextromethorphan. Saturation binding assays revealed that a Ki concentration of dextromethorphan reduces both the Kd and the Bmax of [3H](+)-pentazocine binding to σ1 receptors. Taken together, these data suggest that dextromethorphan exerts some of its antidepressant actions through σ1 receptors.

A clinical investigation of inhibitory effect of panobinostat on CYP2D6 substrate in patients with advanced cancer

Panobinostat is a potent oral pan-deacetylase inhibitor with promising clinical activity in hematologic malignancies. Panobinostat was shown to inhibit CYP2D6 activity in vitro; thus understanding the magnitude of the potential clinical inhibition of panobinostat on co-medications that are CYP2D6 substrates becomes important. This study evaluated the effects of co-administration of panobinostat with a sensitive CYP2D6 substrate, dextromethorphan (DM), in patients with advanced cancer who have functional CYP2D6 genes. Patients received 60mg DM alone on day 1, panobinostat at 20mg alone on days 3 and 5, and both agents on day 8. Plasma concentrations of DM and its metabolite dextrorphan (DX) were determined by liquid chromatography-tandem mass spectrometry following serial blood collections on day 1 (DM alone) and day 8 (in combination with panobinostat). Panobinostat increased DM exposure by 64% [geometric mean ratio (GMR), 1.64 (90% confidence interval (CI), 1.17-2.31)] and DX exposure by 29% (GMR, 1.29 [90% CI, 1.10-1.51]). These results indicated that panobinostat weakly inhibited a sensitive CYP2D6 substrate in cancer patients by increasing DM exposure by less than twofold. Safety monitoring of sensitive CYP2D6 substrates with narrow therapeutic index is recommended when co-administering with panobinostat in future clinical practice.

Randomized Open-Label Drug-Drug Interaction Trial of Dextromethorphan/Quinidine and Paroxetine in Healthy Volunteers

The novel combination of dextromethorphan (DM) and quinidine (Q) [DMQ] has been extensively studied in well controlled clinical trials as treatment for pseudobulbar affect (PBA), and is the first US Food and Drug Administration (FDA)-approved treatment for this indication. The approved dosage of DMQ is DM 20 mg and Q 10 mg twice daily. DM is metabolized via cytochrome P450 2D6 (CYP2D6); Q is a CYP2D6 inhibitor used to increase DM plasma concentrations. Paroxetine is both a substrate and inhibitor of CYP2D6. This trial evaluated the effect of DMQ at a dose of DM 30 mg and Q 30 mg twice daily on the steady-state pharmacokinetics of paroxetine 20 mg daily and the effects of paroxetine on the steady-state pharmacokinetics of DMQ in healthy volunteers. This was an open-label, randomized, parallel-group, 20-day trial. Drug plasma concentrations were analysed following monotherapy and concomitant (DMQ + paroxetine) therapy. Participants were 27 healthy adults who were randomized in a 1 : 1 fashion to one of two groups. Group 1 received paroxetine 20 mg once daily for 12 days to attain steady state, at which point DMQ 30 mg/30 mg twice daily was added for 8 days. Group 2 received DMQ 30 mg/30 mg twice daily for 8 days to attain steady state, at which point paroxetine 20 mg once daily was added for 12 days. The primary endpoints were the 90% confidence intervals (CIs) for the ratio of the area under the plasma concentration-time curve (AUC) during concomitant therapy versus monotherapy. Safety and tolerability measures including adverse events (AEs) were also assessed. The 90% CIs of the AUCs were outside of the predefined range [0.80, 1.25] for all analytes, indicating a drug-drug interaction. In group 1 (n = 14), addition of DMQ to paroxetine resulted in a 30% increase in mean plasma exposure of paroxetine (AUC up to 24 hours). In group 2 (n = 13), addition of paroxetine to DMQ resulted in increases in mean plasma exposure (AUC up to 12 hours) of 50% for DM and 40% for Q, and a decrease of 12.3% for dextrorphan, the metabolite of DM. The incidence of AEs was higher with paroxetine monotherapy and combination therapy, compared with DMQ given alone (30.8% with DMQ alone vs 83.3% following addition of paroxetine, and 78.6% with paroxetine alone vs 64.3% following addition of DMQ). Three subjects discontinued due to AEs, and no serious AEs were reported. The addition of DMQ 30 mg/30 mg twice daily to paroxetine increased steady-state paroxetine plasma concentrations and addition of paroxetine to DMQ 30 mg/30 mg twice daily increased steady-state plasma concentrations of DM and Q, indicating a potential interaction. Thus, patients should be monitored for AEs and dosage adjustment considered when combining these two agents.