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PubMed2000

Absence of the preemptive analgesic effect of dextromethorphan in total knee replacement under epidural anesthesia.

BACKGROUND: Previous studies have shown that dextromethorphan (DM), a N-methyl-D-aspartate (NMDA) receptor antagonist, produces a preemptive analgesic effect on post-operative pain. The aim of this study was to further examine the preemptive analgesic effect of intramuscular (i.m.) DM injection on unilateral total knee replacement (TKR). METHODS: Sixty-four ASA I-III patients scheduled for unilateral TKR surgery were randomly allocated into three groups in a prospective double-blind manner. All patients received epidural anesthesia without any premedication. An initial bolus dose of 2% lidocaine (15-20 mL) followed by a maintenance dose of 8-10 mL/h was decided. Fentanyl (1.5 micrograms/kg) and diazepam (2 mg) were given i.v. before epidural catheter insertion. The epidural catheter was placed via the L2-L3 or L3-L4 interspace and advanced for 5 cm cephalad [corrected]. Patients received i.m. injection of 20 mg chlorpheniramine (CPM) before surgery as control (group C, n = 22). For the study groups, patients were given an i.m. injection containing 40 mg DM and 20 mg CPM, before (group B, n = 22) or after surgery (group A, n = 20), respectively. Postoperation, patients received intravenous morphine by means of a patient controlled analgesia (PCA) device for pain relief. The time to the first pull of PCA trigger, morphine consumption, worse pain scores (resting and incidental), and analgesics related side effects were recorded at 1, 2, 4, 8, 24, 48 and 72 h after surgery. RESULTS: The time from the end of operation to the first PCA trigger were 31.2 +/- 5.2 min in group C, 67.3 +/- 11.1 min in group B (P < 0.05, compared with group C) and 61.8 +/- 7.2 min in group A (P < 0.05, compared with group C) respectively. The relevant pain score at resting, observed at the 8 h postoperatively was respectively 4.2 +/- 0.1 in group C, 3.7 +/- 0.2 in group B (P < 0.05, compared with group C) and 3.4 +/- 0.2 in group A (P < 0.05, compared with group C); and at the 24 h was 3.1 +/- 0.2 in group C, 2.4 +/- 0.2 in group B (P < 0.05, compared with group C) and 2.5 +/- 0.1 in group A (P < 0.05, compared with group C) respectively. There were no significant differences in actual morphine delivery and frequency of PCA triggering at all time among the three groups. Moreover, there was also no significant statistic difference in morphine-associated side effects among the three groups. CONCLUSIONS: In the present study, we failed to observe any preemptive analgesic effect of DM (40 mg, i.m.) on postoperative pain in patients who received TKR under epidural anesthesia, however, DM given either before or after surgery augmented other analgesic (morphine) to offer a better pain relief.

Aged↗

PubMed1997

High performance liquid chromatographic determination of dextromethorphan and its metabolite in human urine.

A reverse-phase high-performance liquid chromatographic method was established for the determination of dextromethorphan (DM) and its metabolite dextrophan (DX) in human urine. The sample was purified by an acid-base extraction followed by HPLC analysis on a phenyl column. The eluate was monitored by fluorescence at 280 nm (excitation) and 310 nm (emission). The limit of detection of DM was 0.023 mg.L-1. The within-day and between-day RSD% of DM and DX were all lower than 5%. The average recovery was 104.78%.

Chromatography, High Pressure Liquid↗

PubMed2000

Postoperative intramuscular dextromethorphan injection provides pain relief and decreases opioid requirement after modified radical mastectomy.

BACKGROUND: Narcotics are still the therapeutic mainstay for postoperative pain relief. However, many unwanted side effects are accompanied. NMDA antagonists have been demonstrated to produce analgesic and antihyperalgesic effects, moreover, to possess potentiated effect of narcotics on postoperative pain management. AIMS: To examine whether postoperative dextromethorphan (DM), an antitussive and also an NMDA antagonist, intramuscular injection (I.M.) reduced pain and analgesic requirement after modified radical mastectomy (MRM). METHODS: Sixty-one patients scheduled for MRM were included and randomly allocated into two groups. For the control group (n=31), patients received chlorpheniramine maleate (CPM, 20 mg) I.M., while in the DM group (n = 30), 40 mg DM containing 20 mg CPM (I.M.) was given at the end of surgery. Meperidine (1 mg/kg, I.M.) was prescribed for postoperative pain relief, if ask. The time to first meperidine injection, total meperidine consumption, worst pain score, bed-rest time, and meperidine-related side effects were recorded for 48 hours postoperation. RESULTS: A longer time to first meperidine injection (20.3 +/- 1.4 vs 1.5 +/- 0.2 hr, p < 0.001) and lower meperidine consumption (10.7 +/- 4.0 vs 70.7 +/- 8.9 mg, p < 0.001) were observed in the DM group than the control group. The average bed rest time was significantly shorter in the DM group than in the control group (18.9 +/- 1.5 vs 23.4 +/- 1.6 hr, p < 0.001). The number of patients who required meperidine injection (6 vs 27, p < 0.005) and meperidine-related side effects were significantly lower in the DM group than in the control group (1 vs 7, p < 0.025). No difference was noted in worst VAS pain score between the DM and the study groups. CONCLUSION: Postoperative DM I.M. injection provided an analgesic effect and reduced meperidine requirement after MRM.

Analgesics, Opioid↗

PubMed1992

High-affinity dextromethorphan and (+)-3-(-3-hydroxyphenyl)-N-(1-propyl)piperidine binding sites in rat brain. Allosteric effects of ropizine.

Dextromethorphan (DM) binds to high- and low-affinity sites in the rat brain. The high-affinity DM binding is inhibited by nonnarcotic antitussives, opipramol and sigma ligands with nanomolar affinities. Computer-assisted modeling of homologous and heterologous competition studies between DM and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP] were performed at pH 8.4. These experiments confirmed the existence of the common high-affinity DM1/sigma 1 site (R1) for which DM and (+)-3-PPP have Kd values of 20 and 10 nM, respectively. DM also binds to a second high-affinity site (R2, Kd, 20 nM) for which (+)-3-PPP has only micromolar affinity. Similarly, (+)-3-PPP binds to another high-affinity site (R3, Kd, 60 nM) for which DM has micromolar affinity. The common high-affinity DM1/sigma 1 site is allosterically modulated by the anticonvulsant ropizine, and is (+)-pentazocine sensitive, as is the homologous site in the guinea pig. However, in the rat the common DM1/sigma 1 site is 10 times smaller than in the guinea pig. This explains the apparently different effects of the allosteric modifiers in both species. The multiplicity of binding sites for DM and (+)-3-PPP resolved in this investigation will help to establish the physiological role and the pharmacological potential of the different sites. Meanwhile, the pharmacological effects of DM and sigma ligands cannot be summarily attributed to any particular binding site or receptor. This investigation also demonstrates that the use of multiple labeled and unlabeled ligands, combined with computer-assisted modeling, is essential to resolve multiple binding sites with similar affinities and to characterize the complex effects of allosteric modifiers.

Allosteric Regulation↗

PubMed1992

[Protective effect of dextromethorphan on the ischemic retinal damage in rabbit].

To investigate the effect of dextromethorphan (DEX), N-methyl-D-aspartate (NMDA) receptor antagonist, on the retinal ischemia, 0.4%DEX hydrobromide was intravenously given to rabbits before, during and after retinal ischemia. Retinal function was monitored by electroretinogram (ERG). Retinal ischemia was induced by increasing intraocular pressure to 130 mmHg for 90 or 120 min. Amplitudes of ERG.b-waves recorded after the 90 min ischemia recovered to 72.5 +/- 9.0% in the DEX group and 38.5 +/- 8.5% in the control group which was given normal saline. The maximal recovery rates of b-wave amplitudes after the 120 min ischemia were 44.0 +/- 7.9% in the DEX group and 21.0 +/- 1.3% in the control group. The recovery rates of the b-wave amplitudes in DEX group were significantly higher than in the control group (p less than 0.01). It was found that the effective dose of DEX was 0.1-0.4%.

Animals↗

PubMed1992

[Delayed treatment with dextromethorphan can reduce ischemic retinal damage in rabbit].

Previous studies have suggested that prophylactic treatment by dextromethorphan (DEX), N-methyl-D-aspartate (NMDA) receptor antagonist can protect the retina against ischemia. To investigate the effect of DEX on the proceeding ischemic retina, 0.1% DEX hydrobromide was intravenously administered in rabbits immediately (group A), 1 hour (group B) or 2 hours (group C) after the release from ischemia induced by increasing intraocular pressure to 130 mmHg for 90 min. Normal saline was infused immediately after the release from ischemia as control rabbits. Retinal function was monitored by recording electroretinogram (ERG). Twenty four hours after the release of ischemia, the recovery rates of ERG.b-wave amplitudes in groups A, B and C were 61.3 +/- 3.3, 52.2 +/- 9.0 and 43.6 +/- 8.4% of the preischemic amplitude, respectively. The recovery rate of the group A was higher than that of the control (41.9 +/- 10.6%), while no significant differences were seen between groups B or C and the control. The results suggest that DEX can protect the retina if it is administered immediately after the release of ischemia.

Animals↗

PubMed1992

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

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

2-Amino-5-phosphonovalerate↗

PubMed1992

A rapid thin layer chromatographic procedure to identify poor and extensive oxidative drug metabolizers in man using dextromethorphan.

A rapid TLC method is presented to distinguish poor oxidative drug metabolizers from extensive oxidative drug metabolizers. Dextromethorphan (1) is used as test probe because it is safe, well characterized, generally available and easy to measure. The method is based on the extraction of 1 and its major oxidative metabolite dextrorphan (2) from urine, followed by separation on a TLC plate and visualized by a combined Marquis/Mandelin reaction. The intensities of the spots are then compared with a series of standard mixtures containing 1 and 2 in a ratio of 0.3 at different concentrations. This value represents the antimode that separates poor from extensive metabolizers, and an individual is identified as a poor metabolizer if the intensity ratio of the two spots from his urine sample is higher than 0.3. The proposed TLC method was cross checked with an HPLC method and found to correctly identify 9 poor metabolizers out of a population of 71 volunteers.

Chromatography, High Pressure Liquid↗

PubMed2003

Influence of methacrylic acid and hydroxypropylmethyl cellulose on the tablet properties and in vitro release of dextromethorphan hydrobromide.

The release of dextromethorphan hydrobromide from matrices containing hydroxypropylmethyl cellulose (HPMC K100LV) and methacrylic acid copolymer (Eudragit L100-55) has been evaluated at different ratios of the polymers. The physicochemical properties (including weight, thickness, crushing strengh, friability and disintegration time) were also determined at 1000, 2000 and 4000 p compression forces. No significant differences in weight uniformity and thickness values were observed between the different formulations. The crushing strength of the tablets increased with increasing compression force and it reached a constant level at 4000 p. The formulations containing only HPMC K100LV resulted in an extended release pattern, however, Eudragit L100-55 alone could not effectively prolong the drug release. A combination of HPMC K100LV and Eudragit L100-55 in a 1:1 ratio at the 40% level provided an almost similar drug release profile than the marketed product.

Acrylic Resins↗

PubMed2004

High-performance liquid chromatographic analysis of dextromethorphan, guaifenesin and benzoate in a cough syrup for stability testing.

A method has been developed for the analysis of a cough syrup containing dextromethorphan, guaifenesin, benzoic acid, saccharin and other components. Forced degradation was also studied to demonstrate that the method could be employed during a stability study of the syrup. Final conditions were phosphate buffer (25 mM, pH 2.8) with triethylamine (TEA)-acetonitrile (75:25, v/v). In such conditions, all the actives, excipients and degradation products were baseline resolved in less than 14 min, and different wavelengths were used for the different analytes and related compounds.

Acetonitriles↗

PubMed1991

Concordance of P450 2D6 (debrisoquine hydroxylase) phenotype and genotype: inability of dextromethorphan metabolic ratio to discriminate reliably heterozygous and homozygous extensive metabolizers.

Debrisoquine-hydroxylase (P450 2D6) not equal to phenotype was determined in 116 individuals using dextromethorphan as the substrate probe. Polymerase chain reaction and restriction fragment length polymorphism analyses were used to detect inactivating mutations in the CYP2D6 gene and assign genotype in all 116 individuals. Using a urinary metabolic ratio (DM/DT) of > or = 0.3 to define poor metabolizer (PM) phenotypes, 96 subjects were extensive metabolizers (EM) and 20 were PMs. The CYP2D6(B) mutation was the most common mutation, present in 18% of phenotypic EM alleles and 66% of the alleles in PM phenotypes. The CYP2D6(A) mutation (8% of PM alleles) and the CYP2D6 gene deletion (2.6% of PM alleles) were found less frequently. Seven different variants of the CYP2D6 gene were found. In subjects with two mutant alleles, genotype correctly predicted the PM phenotype in 100% (n = 13). Overall, genotype agreed with phenotype assignments in 109 of 116 (94%) subjects. Seven subjects with a wild-type allele at the CYP2D6(A) and CYP2D6(B) loci were phenotypic PMs, representing the only discrepant results. These discrepancies could be due to the imprecision of phenotype assignment or to as yet unknown mutations in CYP2D6. Although the median urinary metabolic ratio was significantly lower in homozygous EMs compared with heterozygous EMs, there was extensive overlap in metabolic ratios in these two groups, indicating that the DM/DT metabolic ratio cannot reliably discriminate homozygous EMs from heterozygous EMs.

Adolescent↗

PubMed1991

[Antagonistic effects of dextromethorphan on vasoconstriction of phencyclidine in vitro].

Bioassay and spectrophotofluorometry were used to study the antagonistic effect of dextromethorphan (DM) on phencyclidine (PCP) vasoconstriction in rabbit ear artery. DM (5 mumols.L-1) antagonized enhancement of PCP, N-[1-(2-thienyl) cyclohexyl] piperidine (TCP) and dizocilpine maleate (MK-801) (5 mumols.L-1) on electrical stimulation-induced vasoconstriction by 86 +/- 18%, 84 +/- 17%, and 86 +/- 18%, respectively (n = 6, P less than 0.01), but had no obvious bioactivity itself at the same concentration. DM (1, 2.5, and 5 mumols.L-1) inhibited the PCP effect and reduced the maximal effect of PCP with pD2' = 5.3 +/- 0.3 (n = 4). The contents of norepinephrine (NE) in control, PCP, and DM + PCP groups were 5 +/- 6, 12 +/- 8, and 5 +/- 6 ng.ml-1, respectively (n = 9). PCP (10 mumols.L-1) increased the NE release (P less than 0.05) but DM (10 mumols.L-1) inhibited it (P less than 0.01). The results suggest DM may be a noncompetitive blockader for PCP receptors.

Animals↗

PubMed1989

High affinity dextromethorphan binding sites in guinea pig brain. Effect of sigma ligands and other agents.

Dextromethorphan (DM), a non-narcotic antitussive, binds in the guinea pig brain to specific high- and low-affinity sites with Kd values of 57 nM and 24 microM, respectively (Musacchio et al., 1988). The antitussives carbetapentane, caramiphen, butamirate and dimethoxanate competed with the high-affinity binding of [3H]DM at pH 7.4 with nanomolar Ki values. Sigma site ligands showed high affinity for [3H]DM binding sites. The rank order of potency was: haloperidol greater than (+)-pentazocine greater than (+)-cyclazocine greater than 3-(-3-hydroxyphenyl)-N-(1-propyl)piperidine greater than (+)-N-allylnormetazocine greater than (-)-butaclamol much greater than (+)-butaclamol (-)-N-allylnormetazocine. The antipsychotic perphenazine competed with low nanomolar Ki values, whereas rimcazole was weaker. The antidepressant opipramol and the benzomorphan (+)2'methoxyphenazocine were the most effective drugs tested, with Ki values of 0.4 nM. By contrast, MK-801 and phencyclidine hydrochloride were very weak competitors for [3H]DM binding. The diphenylalkylamines were the most effective competitors of the calcium channel blocking agents: prenylamine and cinnarizine had Ki values of 17 and 22 nM, respectively. Lidoflazine and hydroxyzine were slightly less potent, but nifedipine and the benzothiazepine diltiazem were much weaker. Potassium channel blockers inhibited DM binding in pharmacologically relevant concentrations: primaquine was the most effective with a Ki of 0.5 microM. Other antimalarial potassium channel blockers tested inhibited binding in the micromolar range. 4-Aminopyridine and tetraethylammonium had Ki values of 0.76 and 1.40 mM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Effects of dextromethorphan site ligands and allosteric modifiers on the binding of (+)-[3H]3-(-3-hydroxyphenyl)-N-(1-propyl)piperidine.

Equilibrium binding analysis demonstrated that (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-[3H]3-PPP] binds in guinea pig brain homogenates to high and low affinity sites with Kd values of 25 nM and 0.9 microM, respectively. Competition studies with dextromethorphan (DM) site ligands and other drugs against (+)-[3H]3-PPP demonstrated that their Ki values and rank order of potency are identical to those found previously against [3H] DM. Most significant, ropizine produced a concentration-dependent increase in the binding of (+)-[3H]3-PPP, with an inhibitory component at high concentrations, as described previously for [3H]DM. Similarly, phenytoin increased the binding of (+)-[3H]3-PPP in the same fashion as that of [3H]DM. Computer-assisted analysis of equilibrium binding of (+)-[3H]3-PPP in the presence of 10 microM ropizine demonstrated that the binding increase produced is due to a 3-fold increase in the affinity for (+)-[3H]3-PPP. These results, and our previous finding that sigma ligands inhibit [3H] DM binding with a rank order of potency similar to that for sites labeled with (+)-[3H]3-PPP or (+)-[3H]SKF10,047 strongly suggest that sigma ligands bind to the high affinity DM site. These findings, and the inability of DM and other antitussives to produce psychotomimetic side effects, suggest that the high affinity DM sites can mediate only the nonpsychotomimetic effects of sigma ligands. However, further studies are necessary to determine the physiological role and therapeutic potential of the DM high affinity sites.

Allosteric Regulation↗

PubMed1988

High affinity dextromethorphan binding sites in guinea pig brain: further characterization and allosteric interactions.

Dextromethorphan (DM), a non-narcotic antitussive with anticonvulsant activity, binds to high (Kd, 57 nM)- and low-affinity sites (Kd, 24 microM) in the guinea pig brain. This work, done at physiological pH, expands previous results obtained at pH 8.3. Phenytoin (PHT) produces an allosteric increase in the binding of [3H]DM, which is more marked than that reported previously: PHT (100 microM,) at pH 7.4, increased the binding affinity of [3H]DM to brain homogenates 4-fold, without changing the concentration of DM sites. Moreover, ropizine (SC-13504) an anticonvulsant benzhydryl piperazine, also produced a marked concentration-dependent increase in the binding of [3H]DM, which is mediated by a decrease in the dissociation rate of [3H]DM. Importantly, the effects of ropizine are fully apparent at 10 microM, 10-fold lower than those of PHT. The effects of PHT and ropizine show that the affinity of the DM sites can be increased by other ligands, suggesting that these sites are located on macromolecules that can exist in at least two conformational states. [3H]DM also binds to peripheral tissues, but the brain displays the highest affinity. Besides, the central and peripheral sites are different as determined by competition studies with caramiphen and carbetapentane, which are DM site ligands with antitussive and anticonvulsant activity. The results reported in this communication are consistent with the hypothesis that the high-affinity DM binding sites mediate antitussive and anticonvulsant activity when occupied by the appropriate ligand.

Animals↗

PubMed1986

Effect of dextromethorphan on guinea pig ileal contractility in vitro: comparison with levomethorphan, loperamide and codeine.

Dextromethorphan (DM) was tested for its effect on the contractility of the guinea pig ileum in vitro. Comparisons were made with levomethorphan, levorphanol, codeine and loperamide. DM and codeine inhibited the contractions of the electrically stimulated ileum, with IC50 values of 15 and 8 microM, respectively. The inhibitory effect of DM, in contrast to codeine, was not blocked by the opiate antagonist naloxone. Pretreatment (8, 50 and 100 microM) with DM and its I-isomer levomethorphan reduced in a dose-dependent fashion both phasic and tonic contractions produced by maximally effective concentrations of carbachol and 80 mM KCl. Pretreatment (8, 50 and 100 microM) with codeine, dextrorphan or levorphanol, unlike DM, did not reduce carbachol or KCl-induced contractions. The concentration-response curves to calcium in K+ depolarized ileum were shifted to the right in a parallel manner suggesting competitive antagonism for DM (pA2 5.3), levomethorphan (pA2 5.3) and loperamide (pA2 6.6). Codeine and levorphanol (8, 50 and 100 microM) did not antagonize calcium-induced contractions. In two assays of calmodulin-dependent processes DM was inactive (IC50 greater than 1 mM), whereas trifluoperazine and calmidazolium (standard calmodulin antagonists) were active in the micromolar range. In summary, these data suggest that DM, through a nonopiate mechanism, antagonizes gut contractility possibly by "stabilizing" neuronal and/or muscle cell membranes.

Actins↗

PubMed1983

High-affinity dextromethorphan binding sites in guinea pig brain. I. Initial characterization.

Tritiated dextromethorphan ([3H]DM) binds to two distinct sites in guinea pig brain, a high-affinity site (Kd = 13-20 nM) and a low-affinity site (Kd greater than 200 nM). Binding of [3H] DM to the high-affinity site is rapid, reversible, saturable, proportional to tissue concentration, and pH-dependent. The sites have a protein-like component, since preincubating brain homogenate in the presence of proteolytic enzymes and protein-modifying reagents significantly reduces binding. There is also a progressive loss of binding when brain homogenate is heated to temperatures in excess of 37 degrees. Millimolar concentrations of lithium, calcium, magnesium, and manganese decrease DM binding while sodium, in concentrations as high as 100 mM, has little effect; calcium in micromolar concentrations slightly enhances binding. The pons-medulla and cerebellum contain the highest density of sites. Subcellular localization studies have shown that high-affinity sites are confined almost exclusively to the microsomal fraction. Binding of DM to brain microsomes does not appear to be related to drug-metabolizing enzymes. The characteristics of DM binding suggest that DM sites are not a subclass of opiate receptors. Studies using tritiated dextrorphan as radioligand failed to reveal a high-affinity binding site for in brain.

Animals↗

PubMed1978

Dextromethorphan: radioimmunoassay and pharmacokinetics in the dog.

A specific radioimmunoassay (RIA) for the determination of the widely used non-narcotic antitussive agent, dextromethorphan (DM) in plasma and urine has been developed using an antiserum to DM which was obtained from rabbits following immunization with an albumin conjugate of (+)-3-methoxymorphinan-17-succinyloxyethyl. Specificity of the RIA was achieved by selective extraction of DM from its known metabolites into hexane at pH 6.5 with 86% recovery. Employing tritium labelled-DM as the radioligand the RIA had a limit of sensitivity of about 4 ng/ml of plasma using a 0.5 ml sample. Following I.V. administration of 2 mg/kg of DM to two dogs, the plasma levels of intact DM declined biexponentially; the terminal exponential phase having a half-life of 2.5-3.9 hr. The volume of distribution of the central compartment ranged from 5-6.4 l/kg while the metabolic clearance rate ranged from 2.5-2.6 1/hr/kg. Oral administration of 10 mg/kg of DM in gelatin capsule resulted in peak plasma levels of 50 and 92 ng/ml at 2 hr post-drug. Following both routes of administration, less than 3.5% of the dose was excreted in the urine as intact DM indicating almost complete biotransformation and/or alternate routes of excretion. In one human subject who received 0.5 mg/kg of DM P.O. in a syrup, the plasma levels were less than 1 ng/ml.

Animals↗