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PubMed1988

The simultaneous assay of triprolidine, pseudoephedrine and dextromethorphan in combined preparations by derivative-difference spectrophotometry.

Difference spectrophotometric procedures are described for the assay of triprolidine hydrochloride, dextromethorphan hydrobromide and pseudoephedrine hydrochloride in Actifed preparations. Triprolidine is assayed by the measurement of the difference absorbance at 301 nm between equimolar solutions of the sample extract in 0.1 M sulphuric acid and 0.1 M sodium hydroxide in ethanol (20% v/v). Dextromethorphan and pseudoephedrine are assayed by measurement of the amplitudes in the second and fourth derivative spectra of the difference absorption spectrum of the sample solutions. The measured values are proportional to the concentrations of the drugs. The accuracy, precision and selectivity of the procedures are discussed. Applications of the assay are described for Actifed Compound Linctus, Actifed Syrup and Actifed Tablets.

Journal Article↗
PubMed1988

Determination of dextromethorphan and its metabolites in plasma by dual column liquid chromatography and fluorimetric detection.

Dextromethorphan and its metabolites were determined in plasma by a dual column liquid chromatographic switching system, after a prepurification on Sep-Pak C(18) cartridges. A polar precolumn (CN) and two hydrophobic analytical columns (C(18)) were used with mobile phases optimised regarding trace enrichment, selectivity and speed by the content of organic modifier. Dextromethorphan and its metabolites could be quantified at 5 ng ml(-1) with an intra-assay precision better than 6% (RSD).

Journal Article↗
PubMed1989

Effect of quinidine on the dextromethorphan O-demethylase activity of microsomal fractions from human liver.

1. The kinetics of dextromethorphan O-demethylation were measured in microsomes prepared from five human livers, both in the absence and in the presence of quinidine. 2. For each liver and over the concentration range of dextromethorphan examined (4.2-3400 microM), this reaction involved an enzymatic component of high affinity, with an apparent Michaelis-Menten constant (Km) of 4.6 +/- 1.8 microM (mean +/- s.d.) and a maximum velocity (Vmax) of 4.2 +/- 3.5 nmol mg-1 h-1 (mean +/- s.d.). 3. Quinidine was a potent and competitive inhibitor of the activity of this component (mean Ki +/- s.d. of 0.025 +/- 0.008 microM) as it is for other oxidation reactions which have already been found to co-segregate with the debrisoquine-type polymorphism. 4. With microsomes from four of the five livers studied, there was evidence of a second enzymatic component of activity characterized by a similar Vmax and about 20-fold higher Km compared with the high affinity component. The activity of this low affinity component was unaffected by quinidine in the concentrations studied.

Chromatography, High Pressure Liquid↗
PubMed1997

Metabolism of dextromethorphan in vitro: involvement of cytochromes P450 2D6 and 3A3/4, with a possible role of 2E1.

Dextromethorphan (DMO), a cough suppressing synthetic analog of codeine, undergoes parallel O-demethylation to dextrorphan (DOP), and N-demethylation to 3-methoxymorphinan (MEM), in humans. 3-hydroxymorphinan, a didemethylated metabolite, is formed secondarily. O-demethylation activity is well established as an index reaction for CYP2D6. However, this pathway appears to be mediated by at least two different enzymes in vitro. N-demethylation activity has recently been proposed to reflect CYP3A3/4 activity. We investigated both pathways in vitro with microsomal preparations from three human livers to assess the value of DMO as a probe drug for CYP2D6 and CYP3A3/4, DMO O-demethylation displayed a biphasic pattern with a high-affinity site reflecting CYP2D6 activity (mean Ki for quinidine, 0.1 +/- 0.13 microM). Kinetic parameters for the two O-demethylation mediating enzymes predict an average relative intrinsic clearance (Vmax/K(m) ratio) of 96% of total O-demethylation mediated via the high-affinity enzyme. Thus, in vitro data confirms the usefulness of DMO O-demethylation as an index reaction to monitor CYP2D6 activity. The Eadie-Hofstee plot of DMO N-demethylation was consistent with single-enzyme Michaelis-Menten kinetics (Vmax varying from 3.3 to 6.8 nmol mg-1 min-1, K(m) from 231 to 322 microM). However, ketoconazole, a CYP3A3/4 inhibitor, reduced N-demethylation only by 60% and had a mean Ki an order of magnitude higher (0.37 microM) compared to other pure CYP3A3/4 mediated reactions. Troleandomycin, a mechanism based CYP3A3/4 inhibitor, inhibited MEM formation by an average maximum of 46%, with an IC50 varying from 1 to 2.6 microM. A polyclonal rat liver CYP3A1 antibody inhibited MEM formation only by approximately 50%. Diethyldithiocarbamate (DDC), a mechanism based CYP2E1 inhibitor, reduced MEM formation at concentrations up to 150 microM between 33 and 43%. Chemical inhibitors of CYP2d6 (quinidine), CYP1A1/2 (alpha-naphthoflavone), and CYP2C9 (sulfaphenazole), as well as a goat rat liver CYP2C11 polyclonal antibody (inhibitory against human CYP2C9 and CYP2C19), had minimal effect on MEM formation rate, thus excluding an involvement of any of these enzymes. DMO N-demethylation is only partly mediated by CYP3A3/4, and therefore is not a reliable index reaction for CYP3A3/4 activity either in vitro or probably in vivo.

Animals↗
PubMed1999

Enzymes in addition to CYP3A4 and 3A5 mediate N-demethylation of dextromethorphan in human liver microsomes.

Both indinavir and troleandomycin (CYP3A inhibitors) are incapable of completely inhibiting dextromethorphan metabolism to 3-methoxymorphinan in human liver microsomes. It is hypothesized that CYPs in addition to CYP3A4 and 3A5 contribute to this biotransformation. The effect of CYP-selective inhibitors on the residual 3-methoxymorphinan activity in human liver microsomes (i.e. in the presence of 30 microM indinavir, a selective CYP3A4 and 3A5 inhibitor) was measured to identify these enzymes. At this concentration, indinavir completely inhibited the formation of 3-methoxymorphinan by rCYP3A4 and rCYP3A5. In addition, the formation kinetics of 3-methoxymorphinan in rCYPs was measured. Only CYP2B6, 2C8 and 2C18 were considered likely candidates as contributors to residual 3-methoxymorphinan activity. The residual 3-methoxymorphinan activity was highly correlated with CYP2B6 activity as measured by CYP2B6 antibody (r(2)=0.90, p<0.001) and by orphenadrine (r(2)=0.97, p<0.001), but was not correlated (r(2)=0.12, p>0.05) with CYP2C8 activity. Collectively, these findings suggest that CYP2B6 is a major contributor towards residual 3-methoxymorphinan activity, while CYP2C8 and 2C18 are either minor contributors or do not contribute to this metabolic process.

Antibodies, Blocking↗
PubMed1994

High-dose dextromethorphan in amyotrophic lateral sclerosis: phase I safety and pharmacokinetic studies.

Much interest has focused on the role of glutamate-mediated excitotoxicity in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). We therefore conducted a phase I study of high-dose dextromethorphan (DM) in ALS. DM is a selective, noncompetitive antagonist of the N-methyl-D-aspartate subtype of the glutamate receptor. Thirteen patients were given DM in an escalating dose fashion, to a target of 10 mg/kg/day or the maximum tolerable dose, and then maintained on this dose for up to 6 months. Total daily doses ranged from 4.8 to 10 mg/kg (median, 7 mg/kg). Side effects were dose limiting in most patients. The most common side effects were light-headedness, slurred speech, and fatigue. Detailed pharmacokinetic and neuropsychology studies were performed. This study demonstrates the feasibility of long-term administration of high-dose DM in ALS, as well as in other conditions associated with glutamate excitotoxicity.

Adult↗
PubMed2002

Dextromethorphan for the reduction of immediate and late postoperative pain and morphine consumption in orthopedic oncology patients: a randomized, placebo-controlled, double-blind study.

BACKGROUND: Postoperative pain is mediated centrally by N-methyl-D-aspartate (NMDA) receptors. The beneficial effects of preincision oral dextromethorphan (DM), which is an NMDA antagonist, on postoperative pain and intravenous patient-controlled analgesia (IV-PCA) morphine (MO) consumption have been examined in patients undergoing surgery. The authors investigated 75 patients who underwent surgery for bone and soft tissue malignancies, in whom postoperative pain is more severe compared with patients who undergo general surgery. METHODS: Patients received placebo, DM 60 mg, or DM 90 mg (25 patients per group) before surgery and on each of the two following days in a randomized, double-blind, placebo-controlled manner. Postoperative IV-PCA MO was started when subjective pain intensity was >/= 4/10 (visual score) and lasted for 72 hours. Rescue drugs on demand were oral paracetamol or dipyrone. RESULTS: The patients in the DM60 and DM90 groups similarly experienced 50-80% less pain (P < 0.01) compared with patients in the placebo group, both immediately and up to 3 days postoperatively, as well as a 50% reduction in the estimated overall maximal pain intensity (P < 0.01). Both DM groups consumed 50-70% less MO than the nonmedicated individuals in the placebo group (P < 0.01), and their demand for rescue drugs on the first postoperative day also was significantly lower (P < 0.01). Patients in the DM groups also were sedated less ( approximately 70%; P < 0.01). There were no differences among the groups in terms of when the patients left their beds, when they were discharged home, or the number of overall side effects. CONCLUSIONS: DM is associated with reduced pain intensity, sedation, and analgesic requirements, even in patients undergoing surgery for bone and soft tissue malignancies. A 3-day DM administration neither increased the incidence of side effects nor accelerated ambulation and discharge home.

Adult↗
PubMed2003

Preoperative and postoperative dextromethorphan provides sustained reduction in postoperative pain and patient-controlled epidural analgesia requirement: a randomized, placebo-controlled, double-blind study in lower-body bone malignancy-operated patients.

BACKGROUND: Pain is mediated centrally by N-methyl-D-aspartate (NMDA) receptors. The antinociceptive effects of preincision dextromethorphan (DM), an NMDA antagonist, have been demonstrated in surgical patients under general or epidural anesthesia. The authors investigated the effects of DM on postoperative pain and other parameters in patients undergoing surgery for bone malignancy under standardized combined general and epidural anesthesia using patient-controlled epidural analgesia (PCEA) postoperatively. METHODS: Patients received placebo or DM 90 mg (30 patients per group) in a double-blind manner preoperatively and on each of the two following days. Postoperative PCEA consisted of 1.6 mg ropivacaine plus 4 microg/mL fentanyl both continuously and by demand up to 96 hours, starting when subjective pain intensity was greater than or equal to 4/10 (visual analog score). Rescue drugs on demand (paracetamol or dipyrone orally) were also available. RESULTS: The DM patients experienced about 50% (P < 0.01) less pain than their placebo counterparts for more than 2 postoperative days and they rated their overall maximal pain intensity by one-half that estimated by the placebo-treated patients (P < 0.01). The DM group also consumed 30-50% less epidural analgesics than the total amount consumed by the placebo-medicated group (P < 0.01) and demanded significantly (P < 0.05) fewer rescue drugs on the first postoperative day. They were less sedated (40-60%, P < 0.01) and reported 50% fewer overall side effects (P < 0.05). The groups were similar for the need for urinary catheterization, time of first ambulation, and/or discharge home. CONCLUSIONS: A 3-day DM administration is associated with better pain reduction in patients undergoing surgery for bone malignancy under combined general and epidural anesthesia with postoperative PCEA compared with placebo without increasing side effects.

Adult↗
PubMed1987

Bioavailability evaluation of a controlled-release dextromethorphan liquid.

A randomized, two-way, steady-state crossover study was performed in 24 healthy male volunteers to evaluate the bioavailability of a controlled-release (CR) dextromethorphan (DM) suspension. Only slow and intermediate DM metabolizers were allowed to participate in the study; determination of metabolizer status was performed before study enrollment. Each volunteer was administered 30 mg of an immediate-release (IR) DM solution qid or 60 mg DM as a CR suspension bid for two weeks, for a total daily dose of 120 mg. After a two-week washout period, the subjects were administered the alternate treatment. Blood samples were collected over a 12-hour dosing period on the last day of each treatment and analyzed for DM and its active metabolite, dextrorphan (DP). In addition, urine was collected over the 12-hour steady-state dosing interval and measured for DM and two metabolites. Pharmacokinetic determinations were made from plasma DM and DP data, and total urinary excretion was determined. All comparisons made between the two formulations indicated that the CR DM suspension was bioequivalent to the IR DM solution at steady state, while producing a prolonged release of the drug over time.

Adolescent↗
PubMed1987

The polymorphic metabolism of dextromethorphan.

The ability of healthy male volunteers to metabolize a 30-mg oral dose of dextromethorphan (DM) was studied in 252 Americans. Two blood samples were collected at four and 24 hours after administration of the dose. The resulting plasma was analyzed for unchanged DM. The volunteers were classified as slow, intermediate, or fast metabolizers on the basis of plasma concentrations of DM. Further differentiation of slow and intermediate metabolizers was achieved by comparing the two-point estimates of elimination-rate constants. In the population studied, 84.3% were fast DM metabolizers, 6.8% were intermediate metabolizers, and 8.8% were slow metabolizers. Previous reports have related the slow DM metabolizers to slow debrisoquin metabolizers, but no such correlations have been achieved with intermediate DM metabolizers. These intermediate DM metabolizers may suggest a new polymorphism not related to debrisoquin or may suggest that "debrisoquin gene" regulation is more complex than originally suggested.

Adolescent↗
PubMed1989

Autoradiographic localization of [3H]dextromethorphan in guinea pig brain: allosteric enhancement by ropizine.

Dextromethorphan (DM) is an antitussive with anticonvulsant activity that binds to high- and low-affinity sites in guinea pig brain homogenates. We examined the autoradiographic localization of [3H]DM using the anticonvulsant ropizine, an allosteric modifier that decreases the dissociation rate of [3H]DM. Competition studies demonstrated that the binding to brain sections was identical to that of brain homogenates [Craviso and Musacchio: Mol Pharmacol 23:629-640, 1983b]. Computer-assisted quantitative analysis of the autoradiographic images demonstrated that [3H]DM binds to discrete structures throughout the brain, but with higher density in the midbrain, pons, and medulla oblongata. The most intense labeling was observed in the rhabdoid, dorsal raphe, median raphe, caudal linear raphe nuclei, and cranial motor nerve nuclei. The central gray showed moderate to high-density labeling throughout its entire rostro-caudal extent, with very high binding in the dorsal tegmental nucleus and the locus coeruleus. Moderate and high binding was also seen in several hypothalamic structures. Distinct bands of moderate binding were seen in the pyramidal cell layer of the piriform cortex, the retrosplenial cortex, the granular cell layer of the dentate gyrus, the pyramidal cell layer of the hippocampus, and the Purkinje cell layer of the cerebellum. The striking similarity between the binding distribution of [3H]DM and sigma ligands, plus competition studies in brain homogenate, support the hypothesis that DM and sigma ligands share a common high-affinity binding site [Musacchio et al: Mol Pharmacol 35:1-5, 1989]. The distribution of [3H]DM binding provides possible anatomical substrates for both the antitussive and anticonvulsant actions of DM.

Allosteric Regulation↗
PubMed1979

Ion-pair reversed-phase high-pressure liquid chromatography of cough-cold syrups I: pseudoephedrine hydrochloride, brompheniramine maleate, and dextromethorphan hydrobromide.

Pseudoephedrine hydrochloride (I), brompheniramine maleate (II), and dextromethorphan hydrobromide (III) in a cough-cold sytup were separated and determined by ion-pair reversed-phase high-pressure liquid chromatography. The separation was carried out using a muBondapak C18 column (30 cm x 3.9 mm i.d.) and a mobile phase of acetonitrile-water-acetic acid (40:60:1) with 0.01 N 1-octanesulfonic acid sodium salt and 0.05 N potassium nitrate. Detection was accomplished using a UV detector at 265 nm for I and II; III was monitored at 280 nm. Concentration versus peak height plots in the ranges of 0.37-1.9 mg/ml for I, 0.025-0.126 mg/ml for II, and 0.125-0.625 mg/ml for III were linear. Ten consecutive injections of a mixture gave a percent relative standard deviation of less than 1% for all three components. Average recoveries from laboratory-prepared samples were 100.5% for I, 100.9% for II, and 100.1% for III. No precolumn cleanup was necessary, and the chromatogram was complete in 16 min.

Brompheniramine↗
PubMed1980

Simultaneous high-pressure liquid chromatographic determination of acetaminophen, guaifenesin, and dextromethorphan hydrobromide in cough syrup.

Acetaminophen (I), guaifenesin (II), and dextromethorphan hydrobromide (III) were separated and quantitated simultaneously in cough syrup by high-pressure liquid chromatography. A chemically bonded octadecylsilane stationary phase was used with a mobile phase of 48% (v/v) aqueous methanol. The mobile phase pH was stabilized to 4.2 by adding formic acid--ammonium formate buffer (approximately 0.4%). The internal standard was o-dinitrobenzene. Retention volumes were 4 ml for I, 6 ml for II, 11 ml for the internal standard, and 20 ml for III. Inactive syrup components did not interfere, permitting direct diluted sample injection. Results on active ingredients were essentially 100% of the claim, with standard deviations of +/- 1.5, 1.2, and 2.1% for I, II, and III, respectively.

Acetaminophen↗
PubMed1980

N-Demethylation of dextromethorphan.

In addition to providing an efficient synthesis of 3-methoxymorphinan hydrochloride, the use of 2,2,2-trichloroethyl chloroformate in the N-demethylation of dextromethorphan led to the isolation of two novel zinc salts of 3-methoxymorphinan.

Dealkylation↗
PubMed1984

Quantitative determination of dextromethorphan and three metabolites in urine by reverse-phase high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) method for the quantitation of dextromethorphan (I) and its three metabolites, dextrorphan (II), 3-hydroxy-9 alpha,13 alpha,14 alpha-morphinan (III), and 3-methoxy-9 alpha,13 alpha,14 alpha-morphinan (IV), in urine was developed. For the analysis of nonconjugated compounds, urine samples at pH 11-11.5, containing 3-methoxy-17-methyl-10-oxo-9 alpha,13 alpha,14 alpha-morphinan as an internal standard, were applied to an extraction column, and the compounds were eluted with 10% n-butyl alcohol-hexane. The organic eluant was extracted with 0.1 M HCl, and an aliquot of the acidic extract was analyzed by HPLC utilizing a 5-micron phenyl column (25 X 0.46-cm i.d.) with a mobile phase of 10 mM potassium phosphate-acetonitrile (45:55, pH 4.0); the column effluent was monitored by UV detection at 280 nm. Free and conjugated metabolites in the enzyme-treated urine were analyzed by selective extraction of I and IV with hexane from urine samples at pH greater than 12 and extraction of II and III with 10% n-butyl alcohol-hexane from urine samples at pH 11-11.5. The minimum quantifiable levels of I-IV ranged from 0.017 to 0.09 micrograms of base/mL and from 0.11 to 0.21 micrograms of base/mL in nonhydrolyzed and hydrolyzed urine, respectively.

Chromatography, High Pressure Liquid↗
PubMed1984

Evaluation of high-performance liquid chromatography and gas chromatography for quantitation of dextromethorphan hydrobromide in cough-cold syrup preparations.

A rapid and sensitive high-performance liquid chromatographic (HPLC) procedure is described for the analysis of the antitussive dextromethorphan hydrobromide in several cough-cold syrup preparations and compared with a gas chromatographic (GC) procedure. In the HPLC procedure, the active ingredient is analyzed as the hydrobromide salt by dilution in the mobile phase and separation on a reverse-phase cyano column. In the GC method, the active ingredient is analyzed as the free base, in which an aqueous solution of the antitussive is made alkaline and extracted with dichloromethane before injection onto the GC column. Excellent resolution of the antitussive agent was obtained by both systems; however, the HPLC assay is preferred for routine analysis (RSD 1%), as compared with the GC assay (RSD 4%).

Chromatography, Gas↗