Dextromethorphan inhibits but dextrorphan potentiates behavior induced by PCP and ketamine in rats.
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Animals↗
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[Dextrorphan-binding proteins in the hippocampus of audiosensitive genetically epilepsy-prone rats].
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Acoustic Stimulation↗
Effects of the N-methyl-D-aspartate antagonists on the rise in [Ca2+]i following depolarization in aged rat brain synaptosomes.
The effects of non-competitive NMDA antagonists, MK-801 and dextrorphan in relation to the rise in intracellular Ca2+ concentrations ([Ca2+]i) after stimulation with 15 mM K+ in whole brain synaptosomes from young (3 months old) and aged (24 months old) Fisher344 rats were examined. A fluorescent chelating agent, Rhod-2, was employed to monitor any alterations of K(+)-evoked [Ca2+]i. In young rats, the rise in [Ca2+]i following depolarization was affected by neither dextrorphan (1, 10, 100 microM) nor MK-801 (0.1, 1, 10 microM), while in aged rats, 1 microM dextrorphan and 0.1 microM MK-801 brought about a significant increase in [Ca2+]i following depolarization. In low Mg2+ medium, 10 microM MK-801 and 100 microM dextrorphan significantly inhibited the rise in [Ca2+]i after stimulation with 15 mM K+ in young rats, while neither dextrorphan nor MK-801 could affect the rise in [Ca2+]i significantly in aged rats. When 100 microM NMDA was applied in a medium containing 1.2 mM Mg2+, the rise in [Ca2+]i following depolarization was slightly inhibited by 1 microM MK-801 in young rats, but it was not inhibited significantly by dextrorphan. In aged rats, both 100 microM dextrorphan and 10 microM MK-801 strongly inhibited the rise in [Ca2+]i following depolarization in the presence of 100 microM NMDA. Instead of NMDA, when 100 microM alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), a non-NMDA receptor agonist, was applied, dextrorphan did not inhibit the rise in [Ca2+]i. In low Mg2+ medium, 100 microM NMDA potentiated the inhibitory effect of 10 microM dextrorphan in young rats, while 100 microM dextrorphan or MK-801 did not show any further inhibition by adding 100 microM NMDA. The addition of 100 microM AMPA did not affect the effect of dextrorphan in a low Mg2+ medium in young rats. These results suggest that NMDA antagonist-mediated [Ca2+]i homeostatic system may alter through aging. In addition, the findings that NMDA potentiated the inhibitory effect of NMDA antagonist, which being further potentiated by aging or lowered extrasynaptosomal Mg2+, indicate the possibility that the Mg2+ block to NMDA receptors might be attenuated through aging.
Aging↗
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↗
Omission of the deconjugation step in urine analysis and the unaltered outcome of CYP2D6 phenotyping with dextromethorphan.
The present study was aimed at determining whether the deconjugation step in chemical analysis could be omitted without altering the outcome of phenotyping CYP2D6 with dextromethorphan. This drug and its metabolite, dextrorphan, were assayed by high-performance liquid chromatography (HPLC) in urine. Urinary levels of dextromethorphan and dextrorphan with and without enzymatic (beta-glucuronidase) treatment of urine and the metabolic ratios for dextromethorphan were determined in 45 subjects. Although the enzymatic treatment did not alter the urinary concentration of dextromethorphan in both phenotypes, it increased the urinary concentration of dextrorphan in both poor and extensive metabolizers by 3.7- and 12.8-fold, respectively. A urinary unconjugated dextromethorphan/unconjugated dextrorphan metabolic ratio of 2.00 and a total dextromethorphan/total dextrorphan metabolic ratio of 0.30, respectively, identified three poor metabolizers. Enzymatic treatment decreased the urinary antimode value. Moreover, the urinary metabolic ratio based on unconjugated dextrorphan and dextromethorphan correlated well with that based on assay of total dextrorphan and dextromethorphan (rs = 0.9458, P < 0.001). The results show that urinary analysis of dextrorphan and dextromethorphan omitting the enzymatic deconjugation step is a fast, reliable and sensitive method and could be used for studying CYP2D6 type genetic polymorphism in man.
Adolescent↗
Dextrorotatory opioids induce stereotyped behavior in Sprague-Dawley and Dark Agouti rats.
Dextromethorphan and dextrorphan elicited a stereotyped behavioral syndrome in rats indistinguishable from that produced by PCP and other non-competitive NMDA antagonists. The rank order of potency for the induction of stereotyped behavior in male Sprague-Dawley rats was: MK-801>PCP>(+/-)cyclazocine>dextrorphan>(+/-)ketamine>dextromethorphan. These behavioral potencies were significantly correlated (0.91; P<0.05) with their respective affinities for high affinity [3H]dextrorphan-labelled NMDA receptors in rat forebrain membranes. To address the propensity of dextromethorphan to induce stereotyped behavior, dextrorotatory-opioid induced stereotypies were investigated in female Dark Agouti and female Sprague-Dawley rats. The female Dark Agouti lacks CYP2D1, the cytochrome P450 enzyme which catalyses the oxidative O-demethylation of dextromethorphan to dextrorphan. No differences were observed in either potency or time to peak effect for dextromethorphan to induce stereotyped behavior in the rat strains, suggesting that the affinity of dextromethorphan for NMDA receptors adequately accounts for its ability to induce stereotyped behavior. Female Dark Agouti rats were, however, more sensitive to the effects of dextrorphan, which may reflect differences in the ability of this strain to metabolize dextrorphan. We find no evidence to suggest that dextromethorphan produces a behavioral syndrome in rats that is distinct from that induced by dextrorphan. The commonality between the pharmacologic profiles of these compounds suggests that the abuse potential of dextromethorphan containing antitussive preparations is related to the non-competitive NMDA antagonist activity of dextromethorphan and its metabolites.
Alcohol Oxidoreductases↗
Effects of route of administration on dextromethorphan pharmacokinetics and behavioral response in the rat.
One of the potential problems of using dextromethorphan as a neuroprotective or anticonvulsant agent is the phencyclidine-like behavioral effects that have been attributed to its major metabolite dextrorphan. Because previous behavioral studies of dextromethorphan have generally failed to consider metabolic conversion to this metabolite, the present studies were conducted to examine the effects of route of administration on dextromethorphan pharmacokinetics and locomotor activity in the rat. The bioavailability of dextromethorphan was 1.3-fold lower and the formation of dextrorphan and other metabolites was 3-fold greater after i.p. injection of 30 mg/kg of dextromethorphan as compared to the s.c. route, indicating substantial effect of first-pass metabolism. Plasma dextromethorphan was correlated with brain dextromethorphan (r = 0.84, P < .001), and the brain/plasma concentration ratio was about 6.5. Plasma-free dextrorphan, but not conjugated dextrorphan, was correlated with brain dextrorphan (r = 0.97, P < .001). Tmax of brain dextrorphan was earlier, and Cmax was higher after i.p. injection of dextromethorphan than s.c. administration (60 min vs. 120 min and 1.0 nmol/g vs. 0.2 nmol/g). Dextromethorphan (60 mg/kg i.p.) increased locomotor activity in the rat 60 min postdose, whereas the same dose of dextromethorphan administered by s.c. injection was without effect. These data demonstrate the route-specific effects on the disposition of dextromethorphan and dextrorphan in rat plasma and brain, as well as the behavioral consequence of the difference.
Animals↗
Effect of salicylamide and acetaminophen on dextromethorphan hydrobromide metabolism: possible pharmacological implications.
The effect of salicylamide and acetaminophen on the metabolic fate of dextrorphan, the primary metabolite of dextromethorphan, was studied in vivo in the rat. Plasma dextrorphan levels were measured at 5-min intervals up to 20 min and at longer intervals up to 2 hr after dextromethorphan hydrobromide was administered orally either alone or in combination with salicylamide and acetaminophen. The combination gave rise to higher plasma dextrorphan levels than did dextromethorphan hydrobromide alone at most sampling times. Conjugation of dextrorphan was inhibited almost quantitatively by salicylamide and acetaminophen at the 5-min sampling time. Salicylamide alone increased the plasma dextrorphan levels when it was coadministered with dextromethorphan, but the differences were not statistically significant. The antitussive activity of dextromethorphan hydrobromide in the unanesthetized dog was faster in onset, greater in intensity, and longer in duration when it was coadministered with salicylamide and acetaminophen. It is suggested that salicylamide and acetaminophen may inhibit the metabolic inactivation of dextrorphan, thereby improving the coughinhibiting potential of dextromethorphan hydrobromide.
Acetaminophen↗
Multiple human cytochromes contribute to biotransformation of dextromethorphan in-vitro: role of CYP2C9, CYP2C19, CYP2D6, and CYP3A.
Cytochromes mediating the biotransformation of dextromethorphan to dextrorphan and 3-methoxymorphinan, its principal metabolites in man, have been studied by use of liver microsomes and microsomes containing individual cytochromes expressed by cDNA-transfected human lymphoblastoid cells. In-vitro formation of dextrorphan from dextromethorphan by liver microsomes was mediated principally by a high-affinity enzyme (Km (substrate concentration producing maximum reaction velocity) 3-13 microM). Formation of dextrorphan from 25 microM dextromethorphan was strongly inhibited by quinidine (IC50 (concentration resulting in 50% inhibition) = 0.37 microM); inhibition by sulphaphenazole was approximately 18% and omeprazole and ketoconazole had minimal effect. Dextrorphan was formed from dextromethorphan by microsomes from cDNA-transfected lymphoblastoid cells expressing CYP2C9, -2C19, and -2D6 but not by those expressing CYP1A2, -2E1 or -3A4. Despite the low in-vivo abundance of CYP2D6, this cytochrome was identified as the dominant enzyme mediating dextrorphan formation at substrate concentrations below 10 microM. Formation of 3-methoxy-morphinan from dextromethorphan in liver microsomes proceeded with a mean Km of 259 microM. For formation of 3-methoxymorphinan from 25 microM dextromethorphan the IC50 for ketoconazole was 1.15 microM; sulphaphenazole, omeprazole and quinidine had little effect. 3-Methoxymorphinan was formed by microsomes from cDNA-transfected lymphoblastoid cells expressing CYP2C9, -2C19, -2D6, and -3A4, but not by those expressing CYP1A2 or -2E1. CYP2C19 had the highest affinity (Km = 49 microM) whereas CYP3A4 had the lowest (Km = 1155 microM). Relative abundances of the four cytochromes were determined in liver microsomes by use of the relative activity factor approach. After adjustment for relative abundance, CYP3A4 was identified as the dominant enzyme mediating 3-methoxymorphinan formation from dextromethorphan, although CYP2C9 and -2C19 were estimated to contribute to 3-methoxymorphinan formation, particularly at low substrate concentrations. Although formation of dextrorphan from dextromethorphan appears to be sufficiently specific to be used as an in-vitro or in-vivo index reaction for profiling of CYP2D6 activity, the findings raise questions about the specificity of 3-methoxymorphinan formation as an index of CYP3A activity.
Anti-Infective Agents↗
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↗
Effects of non-competitive NMDA receptor antagonists on reproductive and motor behaviors in female rats.
MK-801 and dextrorphan, selective non-competitive antagonists at N-methyl-D-aspartate (NMDA) receptors, were used to evaluate the effect of NMDA receptor blockade on sexual and motor behaviors in female rats. Ovariectomized rats were treated with estradiol benzoate (EB) for 48 or 72 h followed by progesterone (P) 3.5-4 h before testing the animals for sexual receptivity. After testing for estrous responsiveness, the effect of NMDA antagonists on several motor behaviors was also assessed. Lordosis frequency and intensity were inhibited in animals that received 0.5 mg/kg MK-801 30 min before EB; the same dose of MK-801 was relatively ineffective when administered 24 h after EB. In neither case did MK-801-treated females differ from controls when motor behaviors were assessed after mating tests. When 30 mg/kg dextrorphan, a short-acting NMDA antagonist, was administered 15 min before P, sexual behavior was not blocked. However, both 0.05 mg/kg MK-801 and 30 mg/kg dextrorphan suppressed ongoing female sexual behavior within 30 min in animals made receptive with EB and P. These deficits in sexual behavior were associated with changes in motor performance. MK-801 (0.1 mg/kg) and dextrorphan (30 mg/kg) abolished movement in the vertical dimension (e.g. jumping and rearing). By contrast, the drugs increased movement in the longitudinal (locomotion) and lateral (circling) dimensions. At 0.2 mg/kg, MK-801 blocked movement in both the vertical and longitudinal dimensions; however, it failed to block circling. Only at 0.4 mg/kg did MK-801 inhibit lateral movements and righting reflexes.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of competitive and non-competitive NMDA receptor antagonists in spinal cord injury.
The potential role of N-methyl-D-aspartate (NMDA) receptors in the pathophysiology of spinal cord injury was examined in rats by comparing the effects of the non-competitive NMDA antagonist dextrorphan and the competitive NMDA antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) on the behavioral and anatomical consequences of impact trauma to the spinal cord. Treatment with either dextrorphan or CPP, administered intrathecally 15 min after trauma, significantly improved chronic (4 weeks) behavioral recovery. Treatment with CPP, but not dextrorphan, limited the decline in serotonin below the injury zone, as shown by both immunocytochemistry and high performance liquid chromatography. Beneficial effects of CPP were dose-dependent. Dextrorphan treatment also improved behavioral outcome when the drug was administered intravenously. These studies implicate NMDA receptor-mediated excitotoxins in tissue damage following spinal cord trauma and suggest that NMDA antagonists may be of value in the treatment of acute, clinical spinal cord injury.
Amino Acids↗
Urethane anesthesia reverses the protective effect of noncompetitive NMDA receptor antagonists against cocaine intoxication.
The present experiments examined whether pretreatment with the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, MK-801 and dextrorphan, could antagonize cocaine-induced convulsions and lethality in conscious Sprague-Dawley (SD) rats and whether urethane anesthesia alters the observed interactions. Conscious, restrained male SD rats received continuous i.v. infusions of cocaine hydrochloride (1.25 mg/kg.min) until convulsions and death occurred. Cocaine doses of 21.2 +/- 1.8 and 29.5 +/- 2.5 mg/kg caused convulsions and death, respectively, in saline treated rats (n = 8). Convulsions were absent in MK-801 (1 mg/kg, i.v.; n = 8) pretreated rats; the lethal cocaine dose was 44.0 +/- 2.7 mg/kg (p < 0.05). In contrast, urethane anesthesia (1.2 g/kg, i.p.) decreased the dose of cocaine required to cause toxicity, compared to that in saline controls (24.8 +/- 0.8 mg/kg, n = 13), in MK-801 (2.0 +/- 0.3, n = 7; p < 0.01) and in dextrorphan mg/kg, n = 13), in MK-801 (2.0 +/- 0.3, n = 7; p < 0.01) and in dextrorphan (25 mg/kg, i.v.; 13.1 +/- 1.4, n = 6; p < 0.01) pretreated rats. Pressor responses with little change in heart rate were evident during cocaine infusion in vehicle pretreated rats. Bradycardiac responses were noted to cocaine in groups following NMDA receptor blockade. Reversal of the pressor response to cocaine was noted in MK-801 pretreated animals, while dextrorphan pretreatment moderated cocaine-induced increases in blood pressure. Ventilatory support protected against cocaine lethality in urethane anesthetized rats, indicating that respiratory failure is the proximate cause of death with cocaine infusion. However, artificially ventilated rats, pretreated with MK-801, were more sensitive (lethal cocaine dose, 76.6 +/- 8.0 mg/kg, n = 5) than vehicle pretreated rats (129.4 +/- 15.8 mg/kg, n = 6), indicating that MK-801 may increase both the respiratory and the cardiac toxicity of cocaine in urethane anesthetized rats. Interactions between NMDA receptors and cocaine are modified by urethane anesthesia.
Anesthesia↗
Receptor stereospecificity in opiate-ethanol interaction using the preexposure-conditioned taste aversion (CTA) paradigm.
In the first experiment, rats were conditioned with different doses of levorphanol or dextrorphan to a novel tasting saccharin solution. In the second experiment, rats were either preexposed to levorphanol or dextrorphan and conditioned with either morphine or ethanol to the saccharin solution. The results showed that levorphanol, but not dextrorphan, at 1, 5 and 10 mg/kg doses effectively induced a CTA. Preexposure to the 5 mg/kg dose of levorphanol blocked both morphine- and ethanol-induced CTAs. Dextrorphan at the same dose did not affect the CTAs. These findings are discussed in terms of the involvement of the opiate receptors in opiate-ethanol interaction.
Animals↗
Comparison of single and combination drug treatment strategies in experimental brain trauma.
Effects of single-drug and combination drug treatments were examined in a model of lateral fluid percussion-induced traumatic brain injury (TBI) in rats. Treatments included the opioid receptor antagonist nalmefene, the thyrotropin releasing hormone (TRH) analog YM14673, the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dextrorphan, nalmefene + dextrorphan, YM14673 + nalmefene, YM14673 + dextrorphan, and equal volume saline. Single-dose treatment with nalmefene, YM14673, or dextrorphan at 30 min after trauma each significantly improved behavioral recovery at two weeks as compared with vehicle-treated controls, confirming earlier studies with these agents. No combination treatment was superior to treatment with the most effective individual drug alone. Combination treatment with the TRH analog and the NMDA antagonist resulted in significantly less effectiveness than treatment with either drug alone. These findings indicate the need for preclinical studies to examine potential drug-drug interactions in the treatment of central nervous system (CNS) trauma.
Animals↗
Protective effect of N-methyl-D-aspartate antagonists after focal cerebral ischemia in rabbits.
We studied the efficacy of postischemic, systemic treatment with the N-methyl-D-aspartate (NMDA) receptor antagonists dextromethorphan and dextrorphan in a rabbit model of transient focal cerebral ischemia. Twenty-two rabbits underwent 1-hour occlusion of the left internal carotid and anterior cerebral arteries followed by 4.5 hours of reperfusion before sacrifice. One hour after the onset of ischemia, immediately after removing the arterial clips, the rabbits were blindly assigned to treatment with dextromethorphan (20 mg/kg i.v. loading dose followed by 10 mg/kg/hr maintenance infusion, n = 7), dextrorphan (15 mg/kg i.v. loading dose followed by 15 mg/kg/hr maintenance infusion, n = 7), or an equivalent volume of normal saline alone (n = 8). The maintenance infusion of drugs or saline was continued for the duration of the experiment. The formalin-fixed brains were analyzed with magnetic resonance imaging using coronal T2-weighted images, and ischemic neuronal damage was assessed on standard coronal hematoxylin-and- eosin-stained sections. The area of neocortical ischemic neuronal damage was significantly reduced in the groups treated with dextromethorphan (4.2%, p less than 0.01) and dextrorphan (6.1%, p less than 0.01) compared with the controls (36.2%). Magnetic resonance imaging demonstrated significantly smaller areas of cortical edema in the groups treated with dextromethorphan (14.6%, p less than 0.01) and dextrorphan (8.0%, p less than 0.01) compared with the controls (32.9%). These clinically tested antitussives with NMDA-antagonist properties may have therapeutic value in the treatment of human cerebrovascular disease.
Animals↗
Potential interactions of methylphenidate and atomoxetine with dextromethorphan.
OBJECTIVE: To examine the potential for drug-drug interactions to influence drug metabolism between the attention-deficit/hyperactivity disorder (ADHD) dl-methylphenidate and atomoxetine with dextromethorphan, a probe for interactions involving cytochrome P450 (CYP) 2D6 isoenzyme. DESIGN: In vitro and ex vivo analysis of changes in metabolism of study drugs. SETTING: Laboratory. PATIENTS: Not applicable. INTERVENTIONS: Pooled human liver microsomal fractions prepared at CEDRA Corporation (now CellzDirect, Austin, Tex.) by the standard differential centrifugation method (lot 821-1). Human liver microsomes were pooled from 15 donors. Recombinant CYP 2D6-containing microsomes (Supersomes; lots 20 and 24 BD Gentest; Woburn, Mass.) were prepared from a baculovirus-infected insect cell line that expressed only the human CYP 2D6 isoform. Dextromethorphan, with and without effector, was incubated with pooled human liver and recombinant CYP 2D6-containing microsomes. Atomoxetine and dl-methylphenidate were tested at 0.1x, 1x, and 10x their reported therapeutic concentrations. Paroxetine, a known inhibitor of CYP 2D6, was used as a reference agent, and quinidine was used as a positive control inhibitor of CYP 2D6. MAIN OUTCOME MEASURES: Changes in substrate metabolism indicative of CYP 2D6-mediated interactions. RESULTS: Atomoxetine and paroxetine inhibited the formation of dextrorphan by about 50% in human liver microsomes and by more than 80% in recombinant microsomes; the profiles of atomoxetine and the known 2D6 inhibitor paroxetine were similar. High concentrations of dextromethorphan reversed the inhibition of its metabolism, indicating a competitive mechanism of the interaction. Conversely, dextromethorphan and dextrorphan only modestly inhibited atomoxetine and paroxetine metabolism. dl-Methylphenidate did not inhibit dextrorphan formation in either microsome preparation, and dl-methylphenidate metabolism was unaffected by dextromethorphan or dextrorphan. CONCLUSION: These results demonstrate the potential for in vivo interactions between dextromethorphan and atomoxetine in patients with ADHD. However, they do not support the plausibility of an in vivo interaction between dextromethorphan and dl-methylphenidate.
Adrenergic Uptake Inhibitors↗
Analgesic effects of phencyclidine-like drugs in rhesus monkeys.
Analgesic and discriminative stimulus effects of phencyclidine (PCP), ketamine, dextrorphan, (+)-N-allyl-normetazocine [(+)-SKF 10,047] and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d) cyclohepten-5,10-amine maleate (MK-801) were studied in rhesus monkeys. All five compounds increased in a dose-related manner the latency for monkeys to remove their tails from warm water with the order of potency being MK-801 greater than PCP greater than ketamine greater than (+)-SKF 10,047 greater than dextrorphan. Moreover, these effects were temperature-dependent with larger doses required to produce a maximum response when higher temperatures (i.e., 55 degrees C) were studied. The effects of PCP, ketamine, dextrorphan, (+)-SKF 10,047 and MK-801 were not attenuated by a dose (1.0 mg/kg) of the opioid antagonist quadazocine that antagonized the analgesic effects of the opioid mu agonist alfentanil and kappa agonist U-50,488. MK-801, PCP, (+)-SKF 10,047 and dextrorphan also substituted in a dose-related manner for the ketamine discriminative stimulus (1.78 mg/kg) and their relative potency as discriminative stimuli was the same as their relative potency in the tail withdrawal procedure. The apparent analgesic effects of PCP-like drugs occurred at doses 2- to 8-fold larger than doses required for discriminative stimulus effects and 3- to 10-fold smaller than doses required for anesthesia. These results support the notion that PCP-like drugs produce analgesic effects at subanesthetic doses. Moreover, the analgesic effects of PCP and related drugs in rhesus monkeys were not mediated by actions at the opioid receptors known to be associated with analgesia.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗