Low frequency of dextromethorphan O-demethylation deficiency in a Chinese population.
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Adult↗
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Induction of CYP2D6 in pregnancy.
Expression of the drug-metabolizing enzyme cytochrome P4502D6 (CYP2D6) is predominantly under genetic control, and enzyme-inducing drugs have little influence on its activity. We studied the activity of CYP2D6 during pregnancy. One hundred forty pregnant women were genotyped for CYP2D6. Seventeen of them (four poor metabolizers, seven heterozygous extensive metabolizers, and six extensive metabolizers) were phenotyped with dextromethorphan in late pregnancy and 7 to 11 weeks after parturition. During pregnancy the dextromethorphan/dextrorphan metabolic ratio was significantly reduced (p = 0.0015) among homozygous and heterozygous extensive metabolizers, indicating increased CYP2D6 activity. In contrast, poor metabolizers showed an increased metabolic ratio during pregnancy. These results are consistent with previous findings of a marked increase in metabolism of the CYP2D6 substrate metoprolol during pregnancy. Both studies indicate an increase in CYP2D6 activity during pregnancy, which may be caused by an induction of the CYP2D6 enzyme.
Adult↗
Liquid chromatography-mass spectrometry with ionspray and electrospray interfaces in pharmaceutical and biomedical research.
Electrospray and ionspray techniques use samples that exist as ions or ion-molecule complexes in solution. After the dispersion of the solution into an electrically charged aerosol, the sample ions may escape from the solution into the gas phase in a region that is at atmospheric pressure. The sample ions are transported into the mass analyser which is operated under a high vacuum. Liquid chromatographs can be coupled to electrospray and ionspray interfaces. Flow injection or continuous infusion of a sample solution (both without the use of a separating column) may be preferred over on-line liquid chromatography-mass spectometry in certain applications. Electrospray or ionspray is applicable to polar or ionic samples. Weakly polar and apolar samples are not ionized under electrospray or ionspray conditions. Applications of the techniques are in the fields of drug metabolism, natural product analysis and the determination of high molecular weights through the observation of multiply charged ions.
1-Methyl-4-phenylpyridinium↗
Dextromethorphan in infantile nonketotic hyperglycinemia.
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Dextromethorphan↗
Cell shape of polymorphonuclear leukocytes is influenced by opioids.
The effects of beta-endorphin(beta-End), an endogenous opioid, were tested in vitro on shape changes in polymorphonuclear leukocytes (PMNs). Cell shape changes indicate alterations of the functional status of the cells. Within 2 min, beta-End but not the opioid alkaloid levorphanol or the antagonist, diprenorphine, induced a cell spreading. Subsequently, beta-End and levorphanol (10(-8) M), but not the dextrorotatory isomer, stimulated an elongation of the cells. Both effects of beta-End could be antagonized by diprenorphine in an equimolar concentration. Thus, the effects were stereo-specific and antagonizable. In this test system, the morphological changes evoked by beta-End were equal to the effects of FMLP, a chemotactic substance, used as a reference. Our findings indicate that endogenous opioids might play a role in modulating the initial phase of the PMNs' offensive behaviour, presumably cell adherence and motility.
Cell Adhesion↗
A rapid electron-capture gas chromatographic procedure for the analysis of p-hydroxymephenytoin.
An electron-capture gas chromatographic procedure was developed for detection and quantification of p-hydroxymephenytoin (OHMEP), a metabolite of S-mephenytoin, in human liver microsomal preparations. OHMEP was derivatized with pentafluorobenzoyl chloride (PFBC) under basic aqueous conditions prior to analysis on a gas chromatograph equipped with a capillary column and an electron-capture detector. Dextrorophan was carried through the procedure as internal standard. The structure of the PFB derivative was confirmed using combined gas chromatography-mass spectrometry (GC-MS). The procedure is rapid and reproducible and produces a stable derivative that has excellent chromatographic properties. The limit of detection was less than 5 ng/ml, and the method was applied to extracts of human liver microsomes, which had been incubated with S-mephenytoin [a probe substrate for cytochrome P450 (CYP) 2C19].
Anticonvulsants↗
Evidence for topographical analogy between methionine-enkephalin and morphine derivatives.
Analogues of the endogenous opiate-receptor ligand [5-methionine]enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH) were designed and synthesized for the purpose of testing the proposed similarity in spatial structure between this peptide and morphine derivatives. In the bioassay (inhibition of electrically induced contractions of the mouse vas deferens) [1-O-methyltyrosine,5-methionine]enkephalin, [1-N-methyltyrosine,5-methionine]enkephalin, [4-tryptophan,5-methionine]enkephalin, and [5-methionine sulfoxide]enkephalin possess, respectively, 0.4, 21, 27, and 67% activity of [5-methionine]enkephalin. These morphinomimetic activities correlate well with the opiate receptor affinities determined by displacement of [3H]naloxone in a guinea pig brain membrane preparation. The effects of O-methylation of the tyrosine residue and N-methylation of the terminal amino group on biological activity and receptor affinity support the hypothesis that the latter two moieties in the peptide correspond to the phenol group and the tertiary nitrogen, respectively, in morphine. Determination of the efficiency of energy transfer from tyrosine in position 1 to tryptophan in position 4 in [4-tryptophan,5-methionine]enkephalin from both tyrosine fluorescence quenching and relative enhancement of tryptophan fluorescence by means of a modified procedure permitted the calculation of an average intramolecular tyrosine-tryptophan separation of 10.0 +/- 1.1 A. Inspection of CPK models showed excellent agreement between this value and both the intrafluorophore distance in the 4 leads to 1 and 5 leads to 2 hydrogen bonded betaI-bend models of [4-tryptophan,5-methionine]enkephalin (9-11 A) and the phenol-phenyl separation in the potent morphine derivative 7alpha-(1(R)-hydroxy-1-methyl-3-phenylpropyl)-6,14-endo-ethenotetrahydrooripavine (8-10.5 A). The ensemble of these findings suggests an analogous topography for [5-methionine]enkephalin and morphine-oripavine derivatives.
Animals↗
Morphine elevates levels of cyclic GMP in a neuroblastoma X glioma hybrid cell line.
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Animals↗
Inhibition of drinking by intrahypothalamic administration of morphine.
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Acetylcholine↗
Lower prevalence of the debrisoquin oxidative poor metabolizer phenotype in American black versus white subjects.
Our objective was to determine whether there are differences in debrisoquin hydroxylase (P450IID6) activity between American black subjects and white subjects. Phenotype was assigned in a group of 586 unrelated white and black children with use of dextromethorphan as the substrate probe. Restriction fragment length polymorphism analysis of genomic deoxyribonucleic acid (DNA) was performed in a subset of subjects by use of a full length complementary DNA for P450IID6. Thirty-seven of 480 (7.7%) white children were poor metabolizers compared with 2 of 106 (1.9%) black children (p = 0.03). Among 41 white subjects and 18 black subjects, there were significant differences (p less than 0.05) in two XbaI DNA restriction fragments; the 44 kb fragment was more common and the 29 kb fragment was less common in black versus white extensive metabolizers. There is a lower prevalence of the debrisoquin poor metabolizer phenotype among American black persons, which could have implications for efficacy or toxicity of drugs metabolized by this enzyme, as well as for racial differences in the prevalence of diseases associated with the debrisoquin oxidative phenotype.
Black People↗
Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind-up of the second pain response in healthy male volunteers.
AIMS: The aim of this study was to assess the efficacy of dextromethorphan and ketamine relative to placebo on the acute nociceptive threshold and wind-up of second pain response in healthy male volunteers. METHODS: The trial was a randomized, double-blind, placebo-controlled, three period crossover, double dummy design in 12 healthy male volunteers. During each of the three periods (which were separated by a 1 week washout period) each volunteer received either a single oral dose of 0.7 mg kg(-1) dextromethorphan and placebo to ketamine, or placebo to dextromethorphan followed by a single intravenous injection of 0.375 mg kg(-1) ketamine, or placebo to both dextromethorphan and ketamine. The trial did not schedule administration of both ketamine and dextromethorphan together. Acute nociceptive thresholds and wind-up of second pain were measured in the skin of the thenar eminence of the ventral surfaces of the right and left hands, using a SOMEDIC thermotest apparatus, before and at the estimated tmax for dextromethorphan (i.e. 2.15 h). Blood pressure and heart rate were also monitored before dosing and after the dosing regimen. RESULTS: Neither dextromethorphan nor ketamine had any significant effect on acute nociceptive thresholds on either hand (P>0.05). Moreover, dextromethorphan was without any significant effect (P>0.05) on the wind-up of the second pain response on either hand. The lsmean number of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 15.84 vs 16.48 (-5.52, 4.24) and 11.75 vs 15.25 (-11.89, 4.90) for left- and right-hand, respectively, following dextromethorphan administration. In contrast ketamine produced significant reductions in wind-up to second pain in both the left and right hands (P=0.0002 and 0.0386, respectively). The lsmean numbers of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 28.41 vs 16.48 (6.60, 17.25) and 25.00 vs 15.25 (0.58, 18.93) for left- and right-hand, respectively. CONCLUSIONS: Wind-up of second pain induced by noxious heat is sensitive to intervention by ketamine, which is known to block the NMDA receptor. These data infer that the wind-up phenomenon evoked by noxious heat involves the activation of NMDA receptors. This volunteer model of pain may have utility in the evaluation of agents that modulate their antinociceptive actions via NMDA mechanisms.
Acute Disease↗
Clinical inhibition of CYP2D6-catalysed metabolism by the antianginal agent perhexiline.
AIMS: Perhexiline is an antianginal agent that displays both saturable and polymorphic metabolism via CYP2D6. The aim of this study was to determine whether perhexiline produces clinically significant inhibition of CYP2D6-catalysed metabolism in angina patients. METHODS: The effects of perhexiline on CYP2D6-catalysed metabolism were investigated by comparing urinary total dextrorphan/dextromethorphan metabolic ratios following a single dose of dextromethorphan (16.4 mg) in eight matched control patients not taking perhexiline and 24 patients taking perhexiline. All of the patients taking perhexiline had blood drawn for CYP2D6 genotyping as well as to measure plasma perhexiline and cis-OH-perhexiline concentrations. RESULTS: Median (range) dextrorphan/dextromethorphan metabolic ratios were significantly higher (P < 0.0001) in control patients, 271.1 (40.3-686.1), compared with perhexiline-treated patients, 5.0 (0.3-107.9). In the perhexiline-treated group 10/24 patients had metabolic ratios consistent with poor metabolizer phenotypes; however, none was a genotypic poor metabolizer. Interestingly, 89% of patients who had phenocopied to poor metabolizers had only one functional CYP2D6 gene. There was a significant negative linear correlation between the log of the dextrorphan/dextromethorphan metabolic ratio and plasma perhexiline concentrations (r(2) = 0.69, P < 0.0001). Compared with patients with at least two functional CYP2D6 genes, those with one functional gene were on similar perhexiline dosage regimens but had significantly higher plasma perhexiline concentrations, 0.73 (0.21-1.00) vs. 0.36 (0.04-0.69) mg l(-1) (P = 0.04), lower cis-OH-perhexiline/perhexiline ratios, 2.85 (0.35-6.10) vs. 6.51 (1.84-11.67) (P = 0.03), and lower dextrorphan/dextromethorphan metabolic ratios, 2.51 (0.33-39.56) vs. 11.80 (2.90-36.93) (P = 0.005). CONCLUSIONS: Perhexiline significantly inhibits CYP2D6-catalysed metabolism in angina patients. The plasma cis-OH-perhexiline/perhexiline ratio may help to both phenotype patients and predict those in whom perhexiline may be most likely to cause clinically significant metabolic inhibition.
Aged↗
Opiate receptor mediation of ketamine analgesia.
Previous workers have noted that analgesia produced by ketamine can be antagonized by the narcotic antagonist, naloxone. In order to elaborate further the apparent similarity between ketamine- and narcotic-induced analgesia, the authors examined the effects of ketamine in three standard test systems for the opiate receptor. In a radioligand binding assay using 3H-dihydromorphine, ketamine stereospecifically bound to opiate receptors in rat brain homogenate, (+) ketamine being 2-3 times more potent than the (-) enantiomer of ketamine. In a bioassay for the opiate receptor, using the longitudinal muscle-myenteric plexus of the guinea pig ileum, ketamine inhibited the twitch-like muscular contractions, as do narcotics. However, only the inhibitory effects of (+) ketamine, which in this system also was twice as potent as (-) ketamine, could be partially antagonized by naloxone, suggesting that this enantiomer is responsible for the opiate receptor-related effects of ketamine. In vivo, the authors found that ketamine displaces 3H-etorphine, a potent narcotic, from opiate receptors in regional areas of the mouse brain, especially in the thalamic region, but not in the cortex. The results suggest that a significant mechanism of ketamine-induced analgesia is mediated by opiate receptors.
Analgesics↗
CYP2D6 status of extensive metabolizers after multiple-dose fluoxetine, fluvoxamine, paroxetine, or sertraline.
The aim of this study was to evaluate the CYP2D6 inhibitory effects of four selective rerotonin re-uptake inhibitors (SSRIs). Thirty-one healthy subjects were phenotyped as extensive metabolizers using the dextromethorphan/dextrorphan (DM/DX) urinary ratio as a marker for CYP2D6 activity before and after 8 days of administration of fluoxetine 60 mg (loading dose strategy), fluvoxamine 100 mg, paroxetine 20 mg, or sertraline 100 mg in a parallel-group design. Statistical analysis was performed on log-transformed DM/DX ratios because of variability within and between treatment groups. DM/DX ratios before (DM/DX(BL)) and after (DM/DX(SSRI)) were compared within and between the four SSRI groups. DM/DX(BL) ratios were not significantly different between the four SSRI treatment groups. Comparing within groups, significant differences between DM/DX(BL) and DM/DX(SSRI) were found for the fluoxetine (p < 0.001; ratio values, 0.020 vs. 0.364) and paroxetine (p = 0.0005, ratio values 0.029 vs. 1.085) but not for the fluvoxamine or sertraline groups. Comparing between groups, significant differences in DM/DX(SSRI) ratios were found for fluoxetine versus sertraline (p = 0.0019, DM/DX = 0.364 vs. 0.057), fluoxetine versus fluvoxamine (p < 0.0001, DM/DX = 0.364 vs. 0.019), paroxetine versus sertraline (p = 0.0026, DM/DX = 1.085 vs. 0.057), and paroxetine versus fluvoxamine (p < 0.0001, DM/DX = 1.085 vs. 0.019). No significant differences were noted between the two potent CYP2D6 inhibitors, fluoxetine and paroxetine, or the two weakest inhibitors, fluvoxamine and sertraline. Five subjects in the fluoxetine and four subjects in the paroxetine groups changed to poor metabolizer phenotype (DM/DX > or = 0.3) after treatment. Although CYP2D6 inhibitory effects of fluvoxamine and sertraline did not yield significant differences from baseline, some subjects exhibited DM/DX ratio increases of 150 to 200%. One paroxetine-treated subject did not exhibit any CYP2D6 inhibition. SSRI dose and plasma concentration may be correlated with the extent of CYP2D6 inhibition and should be further investigated.
Adult↗
Nonexocytotic noradrenaline release from rat cardiac synaptosomal-mitochondrial fractions.
Nonexocytotic noradrenaline (NA) release was examined in rat cardiac synaptosomal-mitochondrial fractions prelabeled with [3H]NA (300 nM; 1 h at 37 degrees C). Ischemic conditions (1 mM iodoacetate + 2 mM NaCN; 15 min at 37 degrees C) evoked a Ca(2+)-independent release of [3H]NA from isolated synaptosomes, which represented 33.4% of total content, whereas the release evoked by 56 mM K+ was Ca2+ dependent and represented 5.8% of total content. Tyramine, phencyclidine (PCP), and rimcazole also caused important Ca(2+)-independent releases of [3H]NA (from 12 to 45% of total content) with median effective concentrations (EC50s) of 6.8, 182, and 41.8 microM, respectively. The release responses evoked by ischemic conditions, tyramine, PCP, and rimcazole were mimicked by the delta-receptor ligand, 1,3-ditolyl guanidine (DTG), and blocked by the uptake 1 inhibitor, desipramine (100 microM). The delta 1-receptors ligands, (+)-3-hydroxyphenyl-N-(1-propyl)piperidine ((+)-3-PPP) and (+)N-allylnormetazocine [(+)SKF-10047], were potent blockers of the release of [3H]NA evoked by ischemic conditions but not by PCP or rimcazole. These data indicate that ischemic conditions and PCP/delta 2-receptor ligands induce carrier-mediated NA efflux from cardiac sympathetic nerve terminals, whereas delta 1-receptor ligands produce marked inhibition of the ischemic response.
Animals↗
No effect of the new antidepressant reboxetine on CYP2D6 activity in healthy volunteers.
The effect of the new antidepressant reboxetine on the activity of the cytochrome P450 (CYP) 2D6 isoenzyme was investigated in 10 healthy volunteers using dextromethorphan as a model CYP2D6 substrate. Each volunteer received a single 30 mg oral dose of dextromethorphan on three different occasions separated by an interval of at least 4 weeks: a) in a control session; b) after 1 week of treatment with reboxetine, 8 mg/day; and c) after 1 week of treatment with paroxetine (an inhibitor of CYP2D6 activity) 20 mg/day. Urine was collected over the next 8 hours for the determination of the dextromethorphan/dextrorphan metabolic ratio. All subjects were classified as extensive metabolizers (EM) with a dextromethorphan/dextrorphan ratio < 0.3. There were no notable changes in the urinary dextromethorphan/dextrorphan ratio in the reboxetine phase as compared to the control session. By contrast, there was a statistically significant increase in the metabolic ratio in the paroxetine phase (p < 0.001), with 4 subjects switching to poor metabolizer (PM) phenotype. These results suggest that reboxetine is unlikely to cause clinically significant interactions with substrates of CYP2D6.
Adult↗
Quantification of intraindividual variability and the influence of menstrual cycle phase on CYP2D6 activity as measured by dextromethorphan phenotyping.
Intraindividual variability and the effects of menstrual cycle phase on CYP2D6 activity were evaluated by dextromethorphan phenotyping in 20 Caucasian normal volunteers. Dextromethorphan 30 mg was administered to 10 men every 14 days for 3 months, and to 10 premenopausal women during the mid-follicular and mid-luteal phases of each menstrual cycle for three complete cycles. Urinary dextromethorphan/dextrorphan molar ratios were obtained after an overnight urine collection. Ten women and nine men were extensive metabolizer phenotypes, and one man was a poor metabolizer phenotype (confirmed by genotyping). There was no difference in dextromethorphan metabolic ratios between the mid-follicular (mean +/- SD: 0.00728+/-0.00717) and mid-luteal (0.00745+/-0.00815) phases of the menstrual cycle (P = 0.88). Also, no significant difference was found in the intraindividual variability of the metabolic ratios between the two phases (P = 0.80). No statistically significant sex difference in CYP2D6 activity was found between men (0.00537+/-0.00431) and women (0.00737+/-0.00983) extensive metabolizers (P = 0.84). For all individuals, intraindividual variability in dextromethorphan ratios ranged from 12.1-136.6% with a median of 36.7%. Because hormonal fluctuations within the mid-follicular and mid-luteal phases of the menstrual cycle do not appear to affect CYP2D6 activity, pharmacokinetic or clinical investigations of CYP2D6 substrate activity may not require menstrual cycle phase stratification. Because baseline metabolic ratios may fluctuate an average of 37%, repeat baseline and treatment phenotyping assessments should be obtained for accurate determination of a given drug's effect on CYP2D6 activity when measured by dextromethorphan.
Adult↗
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↗