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PubMed1996

Evidence for native NMDA receptor subtype pharmacology as revealed by differential effects on the NMDA-evoked release of striatal neuromodulators: eliprodil, ifenprodil and other native NMDA receptor subtype selective compounds.

NMDA increases the release of [14C]acetylcholine and [3H]spermidine or of [14C]GABA and [3H]dopamine from rat striatal slices. The pharmacology of these responses suggests that release of dopamine and GABA, acetylcholine, and spermidine is mediated, respectively, by three distinct NMDA receptor subtypes. IC50 values of compounds for the inhibition of dopamine and GABA release were closely matched, suggesting mediation by the same subtype. This receptor was generally more sensitive to all NMDA antagonists tested relative to that controlling acetylcholine or spermidine release (channel blockers, glycine antagonists, competitive antagonists and polyamine antagonists). The receptors controlling acetylcholine and spermidine release were characterised by lower antagonist sensitivity in general, and that controlling spermidine release was further defined by a marked insensitivity to ifenprodil, eliprodil, magnesium, dextromethorphan, dextrorphan, memantine, desipramine and polyamine spider toxins. In binding studies in which the displacement of 2 nM [3H]MK801 was studied in membranes prepared from a number of brain regions (in the presence of saturating concentrations of glutamate, glycine and spermidine) small regional differences in IC50 values were observed for a number of channel blockers, but no compound generated biphasic displacement curves that would allow masking of a particular subtype and it was not possible to detect binding components that were insensitive to memantine, dextrorphan dextromethorphan or desipramine. Ifenprodil produced biphasic displacement curves in the 1-day-old rat cortex and midbrain (with IC50 values of approximately 2 and 70 microM) and both ifenprodil and eliprodil displaced a small proportion (18%) of [3H]MK-801 with high affinity in the adult rat spinal cord. Displacement of [3H]MK801 by these compounds in all other adult brain regions (cortex, striatum, hippocampus, thalamus, pons, medulla, cerebellum) was monophasic and of low affinity. In general the subtype selectivity suggested by the release studies was not mirrored in the binding experiments, probably because of excessive heterogeneity of sites in the membrane preparations and to the subtype selectivity of [3H]MK801 itself.

Animals↗

PubMed1996

Investigation of xenobiotic metabolism by CYP2D6 and CYP2C19: importance of enantioselective analytical methods.

Investigations into the genetic polymorphism of drug metabolism have involved specific models to screen poor and extensive metabolisers of xenobiotics. Debrisoquine, sparteine, S-mephenytoin and dextromethorphan are particularly well known. They have been extensively described in the literature and are used to phenotype human subjects before performing investigations with new drugs which are believed to be under the control of a genetic polymorphism. Dextromethorphan, debrisoquine and sparteine are good substrates for CYP2D6, whereas the S-enantiomer of mephenytoin is a good substrate for CYP2C19, both being two isozymes of cytochrome P-450. In many drugs, the hepatic microsomal oxidative metabolism involving stereogenic centres congregates either with CYP2D6 or with CYP2C19 or, in certain cases, with both of them. The availability of both CYP2D6 from poor and extensive metabolisers and an enantioselective assay would allow genetic polymorphism in drug biotransformation to be investigated in vitro ex vivo at an early stage of drug development before the IND (investigational new drug). Single-dose investigations in vivo can also be performed when only minimal pre-clinical toxicological data are available and produce more reliable results than in vitro studies. This paper focuses on the problem of genetic polymorphism in drug development and specifically discusses some relevant knowledge gained in the last two decades on enantioselective bioassays. Specific examples are given.

Aryl Hydrocarbon Hydroxylases↗

PubMed1996

The role of cytochrome P450 2D6 in the metabolism of moclobemide.

The metabolic fate of moclobemide (Ro 11-1163), a new reversible and selective inhibitor of monoamine oxidase type A (MAO-A), has been assessed in a pilot study in 2 debrisoquine poor metabolizers (PM) and 4 extensive metabolizers (EM) after multiple oral dosings of moclobemide with and without co-medication of dextromethorphan. Absorption and disposition parameters were not different between PM and EM. Concurrent application of dextromethorphan, a selective substrate of CYP2D6, did not affect the pharmacokinetics of moclobemide. These results indicate that the cytochromal isoenzyme CYP2D6 does not play a major role in the metabolic degradation of moclobemide. Limited CYP2D6 activities because of a genetic defect or co-medications with CYP2D6 substrates should therefore not give rise to elevated moclobemide blood levels.

Absorption↗

PubMedDate not supplied

Comparative effects of felbamate and other compounds on N-methyl-D-aspartic acid-induced convulsions and lethality in mice.

Felbamate and selected compounds were evaluated for their ability to protect against N-methyl-D-aspartic acid (NMDA)-induced convulsions and lethality in mice. Convulsions produced by intracerebroventricular administration of NMDA (0.8 micrograms per mouse) were antagonized by felbamate, phenytoin, carbamazepine, phenobarbital, valproate, diazepam, 2-amino-5-phosphonovalergic acid (APV), dextromethorphan and ketamine. NMDA (350 mg kg-1 intraperitoneally) produced 100% lethality in mice. Felbamate, phenytoin, and phenobarbital were ineffective in preventing NMDA-induced lethalities, whereas diazepam, APV, ketamine and dextromethorphan were the most potent compounds in preventing lethalities. Any relationship between the protective effects of felbamate against NMDA-induced seizures and competitive or non-competitive antagonism of NMDA receptor sites, however, cannot be established until further experimentation is carried out.

Animals↗

PubMed1995

Fluvoxamine and fluoxetine: interaction studies with amitriptyline, clomipramine and neuroleptics in phenotyped patients.

The in vivo pharmacokinetic interaction between two selective serotonin reuptake inhibitors (SSRI) (fluvoxamine, fluoxetine) and tricyclic antidepressants (TCAs) (amitriptyline, clomipramine) or neuroleptics (haloperidol, cyamemazine, levomepromazine, propericiazine) was assessed in 29 in-patients. They were phenotyped twice with dextromethorphan and mephenytoin: first in steady state conditions while under treatment with TCAs or neuroleptics; and also 10 days after an associated treatment with fluvoxamine (150 mg day(-1)) or fluoxetine (20 mg day(-1)). A clear and statistically significant increase in the mean urinary metabolic ratio (MR) of dextromethorphan/dextrorphan and in the mean mephenytoin S/R ratio (S/R) was seen with the fluvoxamine and fluoxetine treatment. The mean MR increased from 0.13 to 0.27 (P<0.01) with fluoxetine and from 0.34 to 0.84 with fluvoxamine (P<0.05). The (dextromethorphan) 'extensive metabolizer' phenotype switched to the 'poor metabolizer' phenotype in six patients by the 10-day fluoxetine treatment, and in two patients by the fluvoxamine treatment. The mean S/R increased from 0.24 to 0.34 (P<0.05) with fluoxetine, and from 0.33 to 0.58 (P<0.002) with fluvoxamine. These results are in agreement with the observed modification of TCA plasma levels after the SSRI association. During fluvoxamine treatment, amitriptyline and clomipramine plasma levels (P<0.06 both) tendentially increased, and those of demethylclomiprarnine decreased (P<0.06). Fluoxetine addition lead to a significant increase (P<0.02) of the desmethylclomipramine plasma levels. Fluvoxamine induced a moderate augmentation of the plasma levels of haloperidol and its reduced metabolite and no change in the plasma levels of cyamemazine and levomepromazine. But patients treated with neuroleptics are to few to draw any firm conclusion. This study suggests, that fluoxetine and fluvoxamine differ in their interaction with the metabolism of some other basic psychotropic drugs, by a mechanism which implies CYP2D6 and CYPmeph and possibly other isoformes of cytochrome P-450. Moreover, the interactions produced varied with the TCA prescribed.

Adult↗

PubMed2006

Current and future centrally acting antitussives.

The purpose of this review is to highlight some important issues regarding current centrally acting antitussive drugs as well as discuss the implications of these matters on the development of future cough suppressants. Drugs that act in the central nervous system to inhibit cough are termed centrally acting and this designation is based exclusively on evidence obtained from animal models. This classification can include drugs that act both at peripheral and central sites following systemic administration. These drugs are intended to reduce the frequency and/or intensity of coughing resulting from disorders of any etiology. There are a number of central cough suppressants identified by their efficacy in animal models and the most prominent of these are codeine and dextromethorphan. Although the exact neural elements on which these drugs act are currently unknown, they are thought to inhibit a functionally identified component of the central system for cough known as the gating mechanism. The efficacy of codeine and dextromethorphan in humans has recently been questioned. These drugs are less effective on cough induced by upper airway disorders than in pathological conditions involving the lower airways in humans. The reasons for this difference in antitussive sensitivity are not clear. We propose that sensory afferents from different regions of the airways actuate coughing in humans by antitussive sensitive and insensitive control elements in the central nervous system. This hypothesis is consistent with results from an animal model in which laryngeal and tracheobronchial cough had different sensitivities to codeine. Other factors that may be very important in the action of central antitussive drugs in humans include the role of sensations produced by a tussigenic stimulus as well as plasticity of central pathways in response to airway inflammation. Resolution of these issues in the human will be a challenging process, but one which will lay the foundation for the development of more effective cough suppressants.

Animals↗

PubMed2005

Non-antibiotic treatments for upper-respiratory tract infections (common cold).

OBJECTIVES: To review the seven Cochrane reviews of non-antibiotic treatment for the common cold. METHODS: Each Cochrane review was read and summarized, and results presented as relative risks and, where possible, numbers needed to treat. RESULTS: The main theme that runs through these Cochrane reviews is the variable quality of the primary studies. In general, the reviewers are fairly cautious about the benefits of any of the treatments other than first-dose decongestants and antihistamine-decongestant combinations. For antihistamines alone, the reviewers were clear about the lack of efficacy except in the high-quality studies in which a global improvement in symptoms was noted. Some studies were statistically significant, but the Cochrane reviewers were guarded about how clinically significant they were. For Echinacea, problems were found with the quality of the studies and the wide range of different forms of this substance. Heated humidified air seemed to be effective in the UK and Israel, but not the USA, making definitive statements about efficacy difficult. Over-the-counter medication for cough seemed to have no documented benefit in children under the age of 5 years. Letosteine (a mucolytic) may be effective in children but is not available in the UK. Bisolvon (a mucolytic) was found to be effective for cough in only one study. For older children and adults, dextromethorphan may be effective (two out of three studies showed benefit), and guiafenesin (an expectorant) showed mixed benefit in two trials. Dexbrompheniramine (a sedating antihistamine)/pseudoephedrine (6 mg/120 mg twice daily for 1 week) was significantly more effective than placebo for severity of cough, whereas, in another study, loratadine (a non-sedating antihistamine)/pseudoephedrine (5 mg/120 mg twice daily for 4 days) did not show any difference between the study groups. Vitamin C may have a small role in preventing the common cold, with possibly a greater role in high-intensity physical activity and sub-arctic conditions. Zinc lozenges seemed to be effective, but the issue of unblinding due to taste was a methodological issue of concern to the reviewers. The benefits and harms are calculated as numbers needed to treat for one person to benefit (NNTB) and numbers needed to treat for one person to harm (NNTH), and were calculated by the author. CONCLUSION: Most non-antibiotic treatments for the common cold are probably not effective. The most promising are dextromethorphan, bisolvon and guiaphenesin for cough, antihistamine-decongestant combinations for a wide range of symptoms, nasal decongestants (at least for the first dose) and possibly zinc lozenges.

Adult↗

PubMed2002

The molecular and enzyme kinetic basis for the diminished activity of the cytochrome P450 2D6.17 (CYP2D6.17) variant. Potential implications for CYP2D6 phenotyping studies and the clinical use of CYP2D6 substrate drugs in some African populations.

In this study, the basis for the diminished capacity of CYP2D6.17 to metabolise CYP2D6 substrate drugs and the possible implications this might have for CYP2D6 phenotyping studies and clinical use of substrate drugs were investigated in vitro. Enzyme kinetic analyses were performed with recombinant CYP2D6.1, CYP2D6.2, CYP2D6.17 and CYP2D6.T107I using bufuralol, debrisoquine, metoprolol and dextromethorphan as substrates. In addition, the intrinsic clearance of 10 CYP2D6 substrate drugs by CYP2D6.1 and CYP2D6.17 was determined by monitoring substrate disappearance. CYP2D6.17 exhibited generally higher K(m) values compared to CYP2D6.1. The V(max) values were generally not different except for metoprolol alpha-hydroxylation with the V(max) value for CYP2D6.17 being half that of CYP2D6.1. CYP2D6.1 and CYP2D6.2 displayed similar kinetics with all probe drugs except for dextromethorphan O-demethylation with the intrinsic clearance value of CYP2D6.2 being half that of CYP2D6.1. CYP2D6.17 exhibited substrate-dependent reduced clearances for the 10 substrates studied. In a clinical setting, the clearance of some drugs could be affected more than others in individuals with the CYP2D6(*)17 variant. The CYP2D6(*)17 allele might, therefore, contribute towards the poor correlation of phenotyping results when using different probe drugs in African populations. To investigate effects of CYP2D6(*)17 mutations on the structure of the enzyme, a homology model of CYP2D6 was built using the CYP2C5 crystal structure as a template. The results suggest an alteration in position of active-site residues in CYP2D6.17 as a possible explanation for the reduced activity of the enzyme.

Africa↗

PubMed2003

NMDA receptors modulate morphine-induced hyperthermia.

An accumulating body of evidence indicates that activation of NMDA receptor complexes modulates a number of morphine-induced responses. Because a single injection of morphine increases extracellular glutamate levels and downregulates NMDA receptors, acute morphine appears to increase glutamatergic transmission. On the basis of those data and the fact that morphine and glutamate induce hyperthermia, we investigated whether NMDA receptors modulate the hyperthermic effects of acute morphine in male Sprague-Dawley rats. Subcutaneous injection of morphine (0.1-15 mg/kg) evoked dose-dependent hyperthermia, which was rapid in onset and peaked 45-60 min post-injection. Pretreatment with LY 235959 (0.1-1 mg/kg, s.c.), a highly selective and competitive NMDA antagonist, or dextromethorphan (5-15 mg/kg, s.c.), a noncompetitive NMDA antagonist, attenuated the hyperthermic effect of morphine (4 mg/kg). In contrast, administration of LY 235959 (1 mg/kg) 15 min after morphine (4 mg/kg) did not reverse the hyperthermia. LY 235959 (1 mg/kg) depressed the hyperthermia caused by DAMGO (1 micro g/rat, i.c.v.), a selective mu agonist, confirming that NMDA receptor activation maximizes mu receptor-induced hyperthermia. Neither LY 2359595 nor dextromethorphan by itself significantly altered body temperature. These data indicate that NMDA receptors modulate morphine-induced hyperthermia and suggest that increases in glutamatergic transmission maximize the hyperthermia evoked by morphine.

Animals↗

PubMed1997

Neuroprotective sigma ligands attenuate NMDA and trans-ACPD-induced calcium signaling in rat primary neurons.

The effect of neuroprotective sigma ligands possessing a range of relative selectivity for sigma and phencyclidine (PCP) binding sites on N-methyl-D-aspartate (NMDA) and (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD)-stimulated calcium flux was studied in 12-15-day-old primary cultures of rat cortical neurons. In approximately 80% of the neurons tested, NMDA (80 microM) caused a sustained increase in intracellular calcium ([Ca2+]i). With the exception of R-(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride ((+)-3-PPP) (previously shown not to be neuroprotective) all of the sigma ligands studied significantly altered NMDA-induced calcium dynamics. The primary effect of dextromethorphan, (+)-pentazocine, (+)-cyclazocine, (+)-SKF10047, carbetapentane, 1,3-di(2-tolyl) guanidine (DTG), and haloperidol was to shift the NMDA response from a sustained, to either a biphasic or a transient, calcium event. In contrast to NMDA, the primary response observed in 62% of the neurons treated with trans-ACPD (100 microM) was a transient elevation in [Ca2+]i. Here, however, only the highly selective neuroprotective sigma ligands (i.e., those lacking substantial PCP binding affinity) significantly decreased the number of transient responses elicited by trans-ACPD whereas the PCP-related sigma ligands such as dextromethorphan, (+)-SKF10047 and (+)-cyclazocine were ineffective. Unexpectedly, (+)-3-PPP potentiated trans-ACPD activity. These results demonstrating attenuating effects of sigma ligands on NMDA-stimulated neuronal calcium responses agree with earlier studies using glutamate and KCl and identify a sigma receptor modulation of functional NMDA responsiveness. Furthermore, the ability of sigma ligands to attenuate NMDA-, trans-ACPD- and KCl-evoked neuronal calcium dynamics indicates that the receptor mechanisms mediating sigma neuroprotection comprise complex interactions involving ionotropic, metabotropic, and even voltage-gated calcium signaling processes.

Animals↗

PubMed2000

Cytochrome P-450 activities in human and rat brain microsomes.

The role of cytochrome P450 in the metabolism of dextromethorphan, amitriptyline, midazolam, S-mephenytoin, citalopram, fluoxetine and sertraline was investigated in rat and human brain microsomes. Depending on the parameters, the limit of quantification using gas chromatography-mass spectrometry methods was between 1.6 and 20 pmol per incubation, which generally contained 1500 microg protein. Amitriptyline was shown to be demethylated to nortriptyline by both rat and human microsomes. Inhibition studies using ketoconazole, furafylline, sulfaphenazole, omeprazole and quinidine suggested that CYP3A4 is the isoform responsible for this reaction whereas CYP1A2, CYP2C9, CYP2C19 and CYP2D6 do not seem to be involved. This result was confirmed by using a monoclonal antibody against CYP3A4. Dextromethorphan was metabolized to dextrorphan in rat brain microsomes and was inhibited by quinidine and by a polyclonal antibody against CYP2D6. Only the addition of exogenous reductase allowed the measurement of this activity in human brain microsomes. Metabolites of the other substrates could not be detected, possibly due to an insufficiently sensitive method. It is concluded that cytochrome P450 activity in the brain is very low, but that psychotropic drugs could undergo a local cerebral metabolism which could have pharmacological and/or toxicological consequences.

Aged↗

PubMed2001

A comparison of aroclor 1254-induced and uninduced rat liver microsomes to human liver microsomes in phenytoin O-deethylation, coumarin 7-hydroxylation, tolbutamide 4-hydroxylation, S-mephenytoin 4'-hydroxylation, chloroxazone 6-hydroxylation and testosterone 6beta-hydroxylation.

Aroclor 1254-induced rat liver homogenate supernatant (liver S-9) is routinely used as an exogenous metabolic activation system for the evaluation of mutagenicity of xenobiotics. The purpose of this study is to evaluate whether results obtained with Aroclor 1254-induced liver microsomes would be relevant to human. Aroclor 1254-induced and uninduced rat liver microsomes were compared to human liver microsomes in the metabolism of substrates which are known to be selectively metabolized by the major human cytochrome P450 (CYP) isoforms. The activities studied and the major CYP isoforms involved were as follows: phenacetin O-deethylation (CYP1A2); coumarin 7-hydroxylation, (CYP2A6); tolbutamide 4-hydroxylation (CYP2C9), S-mephenytoin 4'-hydroxylation (CYP2C19); dextromethorphan O-demethylation (CYP2D6); chloroxazone 6-hydroxylation (CYP2E1); and testosterone 6beta-hydroxylation (CYP3A4). We found that both induced and uninduced rat liver microsomes were active in all the pathways studied with the exception of coumarin 7-hydroxylation. Coumarin 7-hydroxylation was observed with human liver microsomes but not the rat liver microsomes. Aroclor-1254 was found to induce all activities measured, with the exception of coumarin 7-hydroxylation. Dextromethorphan O-deethylation activity was higher in the rat liver microsomes than the human liver microsomes. Testosterone 6beta-hydroxylation activity was found to be similar between the human liver microsomes and the induced rat liver microsomes. Our results suggest that experimental data obtained with Aroclor 1254-induced rat liver microsomes may not always be relevant to human.

Animals↗

PubMed1998

CYP2D6 polymorphism is not crucial for the disposition of selegiline.

OBJECTIVE: To determine the possible impact of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of selegiline. METHODS: Five poor metabolizers and 8 extensive metabolizers of debrisoquin (INN, debrisoquine) were given 10 mg selegiline hydrochloride. The concentrations of selegiline and its main metabolites in serum were determined for 4 days. The pharmacodynamics were quantitated by measuring platelet monoamine oxidase type B activity for 3 weeks. In addition, the effect of selegiline and its main metabolites on the CYP2D6-catalyzed dextromethorphan O-demethylase activity and the effect of quinidine on the metabolism of selegiline were studied in human liver microsomes. RESULTS: Peak serum concentrations of selegiline were reached rapidly and ranged from 1 to 32 nmol/L. The metabolite concentrations were considerably higher and remained so for a longer period. There were no significant differences in the pharmacokinetic parameters of selegiline, desmethylselegiline, and l-amphetamine between poor metabolizers and extensive metabolizers. However, the area under the serum concentration-time curve (AUC) values of l-methamphetamine were, on average, 46% higher (P = .01) in poor metabolizers than in extensive metabolizers. No significant correlations were found between debrisoquin metabolic ratio and AUC values of selegiline or its metabolites, except for l-methamphetamine (rs = 0.90; P < .001). The maximum monoamine oxidase type B inhibition was 97% in both groups. The inhibitory potency of selegiline, desmethylselegiline, and l-methamphetamine toward dextromethorphan O-demethylase was very low (50% inhibitory concentration values from 160 to 580 mumol/L). Quinidine (< or = 100 mumol/L) did not inhibit the formation of desmethylselegiline or l-methamphetamine from selegiline. CONCLUSIONS: CYP2D6 is not important in the primary elimination of selegiline, and the biological effect of selegiline seems to be similar in poor metabolizers and extensive metabolizers of debrisoquin. The inhibitory effect of selegiline and its main metabolites on CYP2D6 activity seems to be negligible.

Adrenergic Agents↗

PubMedDate not supplied

The nonnarcotic antitussive drug dimemorfan: a review.

The antitussive dimemorfan phosphate was discovered through extensive screening of morphinic derivatives and was introduced in Japan in 1975. The majority of studies on dimemorfan have been published in Japanese, and this review aims to make these data more generally available. The antitussive action of dimemorfan appears to be directly on the cough center in the medulla. Dimemorfan does not induce any significant physical or psychologic dependence, and its antitussive action is not affected by the opioid-receptor blocker levallorphan. Dimemorfan is therefore considered a nonnarcotic antitussive. Studies of antitussive effects in animal models indicate that dimemorfan is up to three times more potent than codeine and is equivalent to dextromethorphan. Three major comparative clinical trials and postmarketing surveillance studies showed that dimemorfan is equally or slightly more efficacious than dextromethorphan, benproperine phosphate, or placebo for the control of coughing. Several animal and clinical studies have confirmed the efficacy and safety of dimemorfan. Dimemorfan was effective in the majority of patients. In contrast to the narcotic antitussives, dimemorfan caused no serious problems with the digestive system, such as constipation and disorders of the bile duct, caused no dependence or tolerance, and was unlikely to have clinical analgesic effects. Minor side effects, such as loss of appetite, nausea, and drowsiness, were seen in less than 10% of patients. A syrup formulation of dimemorphan that retains its efficacy and safety is also available. Overall, these data indicate that dimemorfan is an effective nonnarcotic antitussive agent with a low incidence of adverse events.

Animals↗

PubMed1999

NMDA receptor antagonists inhibit apomorphine-induced climbing behavior not only in intact mice but also in reserpine-treated mice.

The present study showed that the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, MK-801 {(+)-5-methyl-10,11-dihydroxy-5H-dibenzo-[a,d]-cyclohepten-5,10-im ine hydrogen maleate}, ketamine, dextrorphan and dextromethorphan attenuated apomorphine-induced climbing behavior in reserpine-treated mice. In addition, the competitive NMDA receptor antagonists, D(-)-2-amino-5-phosphonopentanoic acid (AP-5) and D(-)-3-(2-carboxypipera-zine-4-yl)-propyl-1-phosphonic acid (CPP), also inhibited the apomorphine-induced climbing behavior in reserpine-treated mice as well as in intact mice. Previous work in our laboratory had shown that the noncompetitive NMDA receptor antagonists, MK-801, ketamine, dextrorphan and dextromethorphan cause a pronounced inhibition of apomorphine-induced cage climbing behavior in intact mice, suggesting the involvement of NMDA receptors in the glutamatergic modulation of dopaminergic function at the postsynaptic dopamine (DA) receptors. Therefore, the present results strongly support our previous conclusion that the NMDA receptors play important roles in the glutamatergic modulation of dopaminergic function at the postsynaptic DA receptors.

Animals↗

PubMed1998

Effects of gestational and overt diabetes on placental cytochromes P450 and glutathione S-transferase.

Objective: Animal and in vivo human studies have observed that diabetes alters the expression of hepatic metabolizing cytochrome P450 (CYP) and glutathione S-transferase (GST) enzymes. The placenta has the ability to metabolize a number of xenobiotic and endogenous compounds by processes similar to those seen in the liver. Our objective was to compare placental xenobiotic metabolizing activity in diabetics to matched non-diabetic controls to determine if the presence of diabetes alters placental xenobiotic metabolizing activity.Methods: The catalytic activities of 7-ethoxyresorufin-O-deethylation [EROD] (CYP1A1), chlorzoxazone 6-hydroxylation (CYP2E1), dextromethorphan N-demethylation (CYP3A4), dextromethorphan O-demethylation (CYP2D6), and 1-chloro-2,4-dinitrobenzene (CDNB) conjugation with glutathione (GST) from placentas of diet controlled (class A1) and insulin-dependent (class A2) gestational diabetics and overt diabetics were compared to matched controls.Results: No differences in EROD activity were observed among overt or gestational diabetics and their respectively matched controls. CYP2E1, 2D6, and 3A4 enzyme activity were not detected in human placentas. In contrast, GST activity was significantly reduced by 30% (P <.05) in overt diabetics as compared to their matched controls and gestational diabetics.Conclusion: Pregnant women with overt diabetes have reduced GST activity in the placenta, which could potentially result in exposure of the fetus to harmful reactive electrophilic metabolites.

Journal Article↗

PubMed2004

Mechanism-based inactivation of cytochrome P450 2D6 by 1-[(2-ethyl-4-methyl-1H-imidazol-5-yl)methyl]- 4-[4-(trifluoromethyl)-2-pyridinyl]piperazine: kinetic characterization and evidence for apoprotein adduction.

The kinetics for inactivation of cytochrome P450 2D6 by (1-[(2-ethyl-4-methyl-1H-imidazol-5-yl)methyl]-4-[4-(trifluoromethyl)-2-pyridinyl]piperazine (EMTPP) were characterized, and the mechanism was determined in an effort to understand the observed time-based inactivation. Loss of dextromethorphan O-demethylase activity following coincubation with EMTPP followed pseudo-first-order kinetics and was both NADPH- and EMTPP-dependent. Inactivation was characterized by an apparent Ki of 5.5 microM with a maximal rate constant for inactivation (kinact) of 0.09 min(-1), a t1/2 of 7.7 min, and a partition ratio of approximately 99. P450 2D6 inactivation was unaffected by coincubation with exogenous nucleophiles or reactive oxygen scavengers and was protected by the competing inhibitors N-4-(trifluoromethyl)benzyl quinidinium bromide and quinidine. After a 30 min incubation with 100 microM EMTPP, dextromethorphan O-demethylase activity was decreased approximately 76%, with a disproportionate loss ( approximately 35%) in carbon monoxide binding. Additional mechanistic studies showed no evidence of either metabolite inhibitory complex formation or heme adduction. However, a P450 2D6 apoprotein adduct was characterized that had a mass shift relative to unadducted P450 2D6 apoprotein consistent with the molecular mass of EMTPP (353 Da). In vitro metabolism studies revealed that EMTPP is susceptible to P450 2D6-mediated hydroxylation and dehydrogenation, postulated to both form via initial hydrogen atom abstraction from the alpha-carbon of the imidazole ethyl substituent. Additional studies demonstrated that while a dehydrogenated EMTPP metabolite was apparently stable and observable, we propose that a thermodynamic partitioning may exist, which results in formation of a second dehydrogenated imidazo-methide-like metabolite that may serve as the reactive species causing mechanism-based inactivation of P450 2D6. Last, trapping studies with EMTPP yielded an N-acetyl cysteine conjugate, which upon tandem MS and NMR analysis revealed adduction to the alpha-carbon of the imidazole ethyl substituent. Overall, evidence suggests that nucleophilic attack of an imidazo-methide-like intermediate by a P450 2D6 active site residue leads to apoprotein adduction and consequent inactivation.

Cytochrome P-450 CYP2D6 Inhibitors↗

PubMed2000

Effect of sodium benzoate in the treatment of atypical nonketotic hyperglycinaemia.

A 6-month-old girl presented with hypotonia and mild psychomotor retardation. Subsequently, an atypical manifestation of a nonketotic hyperglycinaemia was diagnosed, confirmed by significantly reduced activity of the glycine cleavage system in the liver tissue. After the patient developed hypsarrhythmia and had a single cerebral seizure, treatment with both sodium benzoate and dextromethorphan was started. During the following year, the girl was free of seizures with improvement of the EEG activity and showed retarded but continuously progressing psychomotor development. At the age of 20 months she began to walk freely but had generalized muscular hypotonia and moderate mental retardation. Discontinuation of dextromethorphan medication after one year of treatment did not change the clinical and electroencephalographic status. However, after cessation of sodium benzoate therapy, epileptic activity in the EEG and behavioural changes occurred. These changes disappeared promptly after sodium benzoate therapy was reinstituted. Thus, this case of mild atypical nonketotic hyperglycinaemia with only moderate psychomotor retardation and without epilepsy benefited from treatment with sodium benzoate in terms of electroencephalographic and behavioural changes.

Electroencephalography↗