Chronic stimulation of the sigma-1 receptor ameliorates ventricular ionic and structural remodeling in a rodent model of depression.

AIM: The purpose of the study was to investigate what effects the sigma-1 receptor (S1R) could exert on the cardiac myocyte ion channels in a rodent model of depression and to explore the underlying mechanisms since depression is an independent risk factor for cardiovascular diseases including ventricular arrhythmias (VAs). MATERIALS AND METHODS: To establish the depression model in rats, chronic mild unpredictable stress (CMUS) for 28 days was used. The S1R agonist fluvoxamine was injected intraperitoneally from the second week to the last week for 21 days in total, and the effects were evaluated by patch clamp, western blot analysis, and Masson staining. KEY FINDINGS: We demonstrated that depression was improved after treatment with fluvoxamine. In addition, the prolongation of the corrected QT (QTc) interval under CMUS that increased vulnerability to VAs was significantly attenuated by stimulation of S1R due to the decreased amplitude of L-type calcium current (ICa-L) and the restoration of reduced transient outward potassium current (Ito) resulting from CMUS induction. The S1R also decelerated Ito inactivation and accelerated Ito recovery by activating Ca2+/calmodulin-dependent kinase II. Moreover, the stimulation of S1R ameliorated the structural remodeling as the substrate for maintenance of VAs. All these effects were abolished by the administration of S1R antagonist BD1047, which verified the roles for S1R. SIGNIFICANCE: Activation of S1R could decrease the vulnerability to VAs by inhibiting ICa-L and restoring Ito, in addition to ameliorating the CMUS-induced depressive symptoms and structural remodeling.

Attenuation of compulsive-like behavior by fluvoxamine in a non-induced mouse model of obsessive-compulsive disorder.

The current study evaluated the role of strain and compulsive trait differences in response to fluvoxamine, a common obsessive-compulsive disorder (OCD) drug, in two different mouse strains (BIG1 and BIG2) with a spontaneous compulsive-like phenotype. For compulsive-like nest-building behavior, dose-dependent attenuation of nesting by fluvoxamine was observed for the BIG1 compulsive-like strain during the first hour after administration. No significant differences were found for the BIG2 strain during the first hour, although a dose-dependent trend similar to that in the BIG1 strain was observed. Fluvoxamine dose dependently decreased the number of marbles buried in both strains 1 h after administration. For anxiety-like behaviors in the open field, no significant drug effects were found for the latency to leave the center and the number of line crossings. Significant strain differences were observed, with the BIG2 strain showing higher anxiety-like behaviors and reduced locomotor activity compared with the BIG1 strain. Consequently, this study adds predictive validity to our mouse model of OCD, whereas the anxiety-like differences between the strains add heterogeneity to our mouse model, similar to the heterogeneity observed in OCD.

Effects of the antidepressants desipramine and fluvoxamine on latency to immobility and duration of immobility in the forced swim test in adult male C57BL/6J mice.

The forced swim test in rodents allows rapid detection of substances with antidepressant-like activity, evidenced as a decreased duration of immobility that is produced by the majority of clinically used antidepressants. Antidepressants also increase the latency to immobility, and this additional measure reportedly can increase the sensitivity of the forced swim test in mice. Extending these findings, the present study examined the effects of desipramine and fluvoxamine in a forced swim test in C57BL/6J mice, a strain commonly used as background for genetic modifications, analyzing results with a method (i.e. survival analysis) that can model the skewed distribution of latencies and that can deal with censored data (i.e. when immobility does not occur during the test), in comparison with the more traditional Student's t-test. Desipramine increased the latency to immobility at 32 mg/kg, but not at lower doses. Fluvoxamine also did not affect latency at lower doses, but in contrast to desipramine, fluvoxamine decreased the latency to immobility at the highest dose (i.e. 32 mg/kg). At doses affecting latency to immobility, neither desipramine nor fluvoxamine significantly affected duration of immobility. Together, these results are generally consistent with the suggestion that inclusion of the latency measure can increase the sensitivity of the forced swim test to detect antidepressant-like effects in mice.

Investigation of a Potential Pharmacokinetic Interaction Between Nebivolol and Fluvoxamine in Healthy Volunteers.

PURPOSE: To investigate whether fluvoxamine coadministration can influence the pharmacokinetic properties of nebivolol and its active hydroxylated metabolite (4-OH-nebivolol) and to assess the consequences of this potential pharmacokinetic interaction upon nebivolol pharmacodynamics. METHODS: This open-label, non-randomized, sequential clinical trial consisted of two periods: Period 1 (Reference), during which each volunteer received a single dose of 5 mg nebivolol and Period 2 (Test), when a combination of 5 mg nebivolol and 100 mg fluvoxamine was given to all subjects, after a 6-days pretreatment regimen with fluvoxamine (50-100 mg/day). Non-compartmental analysis was used to determine the pharmacokinetic parameters of nebivolol and its active metabolite. The pharmacodynamic parameters (blood pressure and heart rate) were assessed at rest after each nebivolol intake, during both study periods. RESULTS: Fluvoxamine pretreatment increased Cmax and AUC0-∞  of nebivolol (Cmax: 1.67 ± 0.690  vs 2.20 ± 0.970  ng/mL; AUC0-∞: 12.1 ± 11.0  vs 19.3 ± 19.5  ng*h/mL ) and of its active metabolite (Cmax: 0.680  ± 0.220  vs 0.960 ± 0.290  ng/mL; AUC0-∞: 17.6 ±20.1  vs 25.5 ± 29.9  ng*h/mL). Apart from Cmax,AUC0-t and AUC0-∞, the other pharmacokinetic parameters (tmax, kel and t½) were not significantly different between study periods. As for the pharmacodynamic analysis, decreases in blood pressure and heart rate after nebivolol administration were similar with and without fluvoxamine concomitant intake. CONCLUSIONS: Due to enzymatic inhibition, fluvoxamine increases the exposure to nebivolol and its active hydroxylated metabolite in healthy volunteers. This did not influence the blood pressure and heart-rate lowering effects of the beta-blocker administered as single-dose. However, more detail studies involving actual patients are required to further investigate the clinical relevance of this drug interaction. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Development of a Physiologically Based Pharmacokinetic/Pharmacodynamic Model to Predict the Impact of Genetic Polymorphisms on the Pharmacokinetics and Pharmacodynamics Represented by Receptor/Transporter Occupancy of Central Nervous System Drugs.

BACKGROUND: Genetic polymorphisms are major determinants of individual variability in a drug's efficacy and safety, which is one of the main challenges in current clinical practice and drug development. The aim of this work was to develop a physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) model to predict changes in the PK parameters associated with genetic polymorphisms and the impact of these changes on drugs' PD effect. METHODS: We developed PBPK models for two central nervous system (CNS) medications, namely quetiapine and fluvoxamine that are substrates for polymorphic enzymes by incorporating the corresponding alterations in the enzyme activity and/or abundance. Then, the PBPK models were linked to PD models to predict the influence of these changes on the drugs' PD effect. RESULTS: Application of the PBPK models for prediction of phenotypic differences in the PKs compared favorably with reported clinical data. In addition, the PBPK/PD models were able to describe the relationship between the drugs' PD effect and their unbound fractions in the brain and predict changes in receptor/transporter occupancy percentages, obtained from positron emission tomography occupancy studies, associated with genetic variations. CONCLUSIONS: This work provides a simplified approach to predict the influence of genetic polymorphisms on the PK parameters and associated PD effect for CNS drugs. The impact of these polymorphisms on the drugs' PD requires further in vivo validation.

Dynamic and Static Simulations of Fluvoxamine-Perpetrated Drug-Drug Interactions Using Multiple Cytochrome P450 Inhibition Modeling, and Determination of Perpetrator-Specific CYP Isoform Inhibition Constants and Fractional CYP Isoform Contributions to Victim Clearance.

Fluvoxamine-perpetrated drug-drug interactions (DDIs) of victims metabolized by multiple cytochrome P450 isoforms (CYP1A2, CYP2C19, and CYP3A4) were simulated using 2 compartment-based tube modeling, assuming a multiple inhibition-constant (Ki) model, as well as a previously reported single Ki model. Good fittings were obtained for all DDIs using consistent perpetrator-specific CYP isoform Kis and fractional CYP isoform contributions to victim clearance in concordance with literature information. Through these simulations, the following rules to predict DDI were derived. Overall enzymatic inhibitory activity calculated from static DDI data determines entirely dynamic DDIs. DDI-relevant time-dependent hepatic blood unbound perpetrator levels can be approximated to mean hepatic blood unbound perpetrator levels in any victim DDIs when a perpetrator is supplied consistently. Static and dynamic multiple CYP model-based simulations agree with one another. Fluvoxamine-perpetrated DDIs can be bridged to other perpetrator DDIs. The derived rules will allow simpler prediction of DDIs from in vivo DDI databases. Tens or hundreds of Ki gaps between in vitro and in vivo data could be reduced to within severalfold using the liver-microsome contamination model, thus suggesting that microsomes qualified with contamination would greatly improve prediction of DDIs from in vitro data.

Identification of CYP2C19 inhibitors from phytochemicals using the recombinant human enzyme model.

The aim of the present study was to develop the recombinant insect cell-expressed protein as an in vitro model for inhibitors screening for human cytochrome P450 2C19 (CYP2C19), and to use the model to investigate the inhibition effect of three phytochemicals on CYP2C19 in vitro. Omeprazole was applied as the probe substrate. The estimated inhibitory constant (K(i)) of ticlopidine and fluvoxamine were 0.64 +/- 0.025 microM and 0.29 +/- 0.090 microM, respectively. After co-incubation with ticlopidine or fluvoxamine, the mean omeprazole Michaelis-Menten constant (K(m)) increased from 4.99 +/- 0.22 microM to 16.25 +/- 1.22 microM or 19.20 +/- 1.73 microM, respectively, while omeprazole's mean V(max) did not vary much. Both ticlopidine and fluvoxamine were competitive inhibitors of CYP2C19. The IC50 of three phytochemicals, isoalantolactone, curcumol and schisandrin A was determined as 38.91 microM, 121.0 microM and 86.41 microM, and the K(i) as 5.02 +/- 1.04 microM, 35.84 +/- 8.95 microM, and 4.46 +/- 0.017 microM, respectively. The in vitro model for inhibitor screening established using recombinant CYP2C19 could be used to assess the inhibition potential of drug candidates. Isoalantolactone and schisandrin A are potent inhibitors of CYP2C19, while curcumol is a moderate potent inhibitor of CYP2C19.

[Protein quality control and psychiatric disorder--involvement of sigma-1 receptor].

The protein quality control mechanism in the endoplasmic reticulum is referred to as the unfolded protein response (UPR), and its failure may be involved in the onset of some psychiatric disorders. We showed that induction of the sigma-1 receptor plays a role in the UPR, and suggested the possibility that this mechanism is impaired in disorders such as schizophrenia. We also demonstrated that fluvoxamine induces expression of the sigma-1 receptor. Therefore, it has the potential to be developed as a drug which exerts an anti-ER-stress effect, i. e., protein quality control effect.

Effects of PB190 and PB212, new σ receptor ligands, on glucocorticoid receptor-mediated gene transcription in LMCAT cells.

The hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) axis is often observed in patients with major depression. It has even been implicated in the pathophysiology of this disease. Some antidepressant drugs (ADs) inhibit glucocorticoid receptor (GR) function under in vitro conditions. The σ(1) receptor agonists reveal potential antidepressant activity in animals, moreover, igmesine is promising as an AD in humans. As already shown, σ receptors are involved in stress-induced responses (e.g., conditioned fear stress in mice). The aim of the present study was to find out whether the new selective σ receptor ligands, PB190 and PB212, are able to affect directly the endocrine system activity. To this end, we evaluated their influence on GR function in mouse fibroblast cells (L929), stably transfected with mouse mammary tumor virus-chloramphenicol acetyltransferase (MMTV-CAT) plasmid (LMCAT cells). Fluvoxamine, a selective serotonin reuptake inhibitor, recognized as a σ(1) receptor agonist was used for comparison. The obtained results showed that both PB190 and PB212 (potential σ(1) receptor agonist and antagonist, respectively) like fluvoxamine, decreased the corticosterone-induced CAT activity in a concentration-dependent manner. The significance of this fact remains ambiguous and requires further studies.

Sertraline increases extracellular levels not only of serotonin, but also of dopamine in the nucleus accumbens and striatum of rats.

Selective serotonin reuptake inhibitors (SSRIs) are a first-line treatment for depression. Recent reports in the literature describe differences in antidepressant effects among SSRIs. Although each SSRI apparently has different pharmacological actions aside from serotonin reuptake inhibition, the relations between antidepressant effects and unique pharmacological properties in respective SSRIs remain unclear. This study was designed to compare abilities of three systemically administered SSRIs to increase the extracellular levels of serotonin, dopamine, and noradrenaline acutely in three brain regions of male Sprague-Dawley rats. We examined effects of sertraline, fluvoxamine, and paroxetine on extracellular serotonin, dopamine, and noradrenaline levels in the medial prefrontal cortex, nucleus accumbens and striatum of rats using in vivo microdialysis. Dialysate samples were collected in sample vials every 20 min for 460 min. Extracellular serotonin, dopamine, and noradrenaline levels were determined using high-performance liquid chromatography with electrochemical detection. All SSRI administrations increased extracellular serotonin levels in all regions. Only sertraline administration increased extracellular dopamine concentrations in the nucleus accumbens and striatum. All SSRI administrations increased extracellular noradrenaline levels in the nucleus accumbens, although fluvoxamine was less effective. These results suggest that neurochemical differences account for the differences in clinical antidepressant effects among SSRIs.

Metabolism of ramelteon in human liver microsomes and correlation with the effect of fluvoxamine on ramelteon pharmacokinetics.

Ramelteon is a melatonin receptor agonist used as a treatment for insomnia. It is subject to a remarkably large drug-drug interaction (DDI) caused by fluvoxamine coadministration, resulting in a more than 100-fold increase in exposure. The objective of this study was to determine whether the DDI could be estimated using in vitro metabolism data. Ramelteon was shown to undergo hydroxylation in human liver microsomes to eight metabolites via six pathways. The main routes of metabolism included hydroxylation on the ethyl side chain and the benzylic position of the cyclopentyl ring, as assessed through enzyme kinetic measurements. Hydroxylation at the other benzylic position was observed in human intestinal microsomes. Ramelteon metabolism was catalyzed by CYP1A2, CYP2C19, and CYP3A4 as shown through the use of recombinant human cytochrome P450 enzymes and specific inhibitors. In liver, CYP1A2, CYP2C19, and CYP3A4 were estimated to contribute 49, 42, and 8.6%, respectively, whereas in intestine only CYP3A4 contributes. The in vitro data were used to estimate the magnitudes of DDI caused by ketoconazole, fluconazole, and fluvoxamine. The DDIs caused by the former were reliably estimated (1.82-fold estimated versus 1.82-fold actual for ketoconazole; 2.99-fold estimated versus 2.36-fold actual for fluconazole), whereas for fluvoxamine it was underestimated (11.4-fold estimated versus 128-fold actual). This suggests that there may be a limit on the magnitude of DDI that can be estimated from in vitro data. Nevertheless, the example of the fluvoxamine-ramelteon DDI offers a unique example wherein one drug can simultaneously inhibit multiple enzymatic pathways of a second drug.

Cognition and depression: the effects of fluvoxamine, a sigma-1 receptor agonist, reconsidered.

Cognitive impairment is a primary feature of patients with major depressive disorder (MDD) and is characterised by stress-induced neural atrophy. Via alpha-adrenergic, anti-cholinergic and anti-histaminic activities, several antidepressants can cause significant counter-therapeutic cognitive impairment. Evidence is emerging of the involvement of sigma-1 receptor agonism in the mechanism of action of some antidepressants, notably fluvoxamine. Sigma-1 receptors are abundant in areas affected by depression/stress-induced cerebral atrophy and their ligands have a unique pharmacological profile; they may promote neurogenesis and initiate adaptive neural plasticity as a protection/reaction to stress. Fluvoxamine, as a potent sigma-1 receptor agonist, has shown ameliorating effects in animal models of psychosis, depression, stress, anxiety, obsessive-compulsive disorder (OCD) and aggression and has been shown to improve cognitive impairments. In humans, fluvoxamine may repair central nervous system (CNS) atrophy and restore cognitive function. The current review explores the mechanisms through which sigma-1 receptors can modulate cognitive function and examines how antidepressant therapy with fluvoxamine may help improve cognitive outcomes in patients with depression.

Protein binding-dependent decreases in hERG channel blocker potency assessed by whole-cell voltage clamp in serum.

In vitro hERG blocking potency is measured in drug discovery as part of an integrated cardiovascular risk assessment. Typically, the concentrations producing 50% inhibition are measured in protein-free saline solutions and compared with calculated free therapeutic in vivo Cmax values to estimate a hERG safety multiple. The free/unbound fraction is believed responsible for activity. We tested the validity of this approach with 12 compounds by determining potencies in voltage clamp studies conducted in the absence and presence of 100% dialyzed fetal bovine serum (FBS). Bath drug concentrations in saline solutions were measured to account for loss of compounds due to solubility, stability, and/or adsorption. Protein binding in dialyzed FBS was measured to enable predictions of serum IC50s based on the unbound fraction and the saline IC50. For 11 of 12 compounds, the measured potency in the presence of dialyzed FBS was within 2-fold of the predicted potency. The predicted IC50 in dialyzed FBS for one highly bound compound, amiodarone, was 9-fold higher than the measured serum IC50. These data suggest that for highly bound compounds, direct measurement of IC50s in the presence of 100% serum may provide a more accurate estimate of in vivo potencies than the approach based on calculated serum shifts.

Tiagabine augmentation to fluvoxamine-risperidone combination in the treatment of obsessive-compulsive disorder.

Despite the recent progress in the pharmacological treatment of obsessive-compulsive disorder (OCD)--especially with high doses of serotonin reuptake inhibitors, alone or in combination with low doses of antipsychotics--a non-negligible proportion of patients remains refractory to it. For these patients augmentation tactics with drugs from other chemical classes, including antiepileptic drugs, seems advisable. We report on the case of a female inpatient with OCD, whereby the adjunction of tiagabine, a selective GABA reuptake inhibitor at 15 mg/day, to a fluvoxamine (400 mg/day)-risperidone (1 mg/day) combination led to the patient's marked improvement as reflected in the reduction by almost 47% of her score on the Yale-Brown Obsessive Compulsive Scale. With respect to tiagabine's specifically anti-OCD mechanism of action, we note that enhanced inhibitory GABAergic neurotransmission slows down excitatory glutamatergic transmission in the cortico-striato-thalamic system, which presumably constitutes the core pathophysiological mechanism of OCD symptoms.

Characterization of drug-protein binding process by employing equilibrium sampling through hollow-fiber supported liquid membrane and Bjerrum and Scatchard plots.

The technique equilibrium sampling through membrane (ESTM) was extended to measuring the free drug concentration in solutions of drug and protein. Bjerrum and Scatchard plots were employed for characterizing individual drug binding to pure human blood proteins. Four drugs were investigated as a model system: fluvoxamine and ropivacaine which dominantly bind to alpha-acid glycoprotein (AGP), and R,S-ibuprofen and S-ketoprofen which highly bind to human serum albumin (HSA). The level of drug binding to AGP and HSA relied on drug and protein concentrations. Bjerrum and Scatchard plots revealed high affinity constants (Ka) at low protein concentration. Both Bjerrum and Scatchard plots of fluvoxamine and ropivacaine binding to AGP showed one specific binding site (n1=1) with ropivacaine Ka value close to 5 times higher than the Ka of fluvoxamine at 22.9 microM AGP concentration. Bjerrum plots of ketoprofen and ibuprofen gave total number of binding sites or bound molecules of 6-7, which did not depend on the drug or protein concentration. Scatchard plots of ketoprofen and ibuprofen exhibited two binding sites (n1 and n2) at 0.15 microM and 0.75 microM HSA concentrations. On one hand, at 0.15 microM HSA, ketoprofen and ibuprofen were bound to site I at n1=1.2 and n1=1.0, respectively. However, at 0.75 microM HSA, ketoprofen and ibuprofen were bound to site I at n1=1.2 and n1=1.9, respectively. On the other hand, site II, at 0.15 microM HSA, interacted with ketoprofen and ibuprofen at n2=5.6 and 6.7, respectively. However, at 0.75 microM HSA, site II interacted with ketoprofen at n2=7.4 and ibuprofen at n2=6.2. It would be concluded that, upon mixing ketoprofen and ibuprofen in a HSA solution, a ketoprofen-ibuprofen interaction would most likely occur at site II in HSA.

Molecular modeling of two CYP2C19 SNPs and its implications for personalized drug design.

CYP2C19 is an important member of the cytochrome P-450 enzyme superfamily and plays a significant role in the drug metabolism. In order to gain insights for developing personalized drugs, the structure-activity relationships of two SNPs, W120R and I331V, with the ligands of CEC, Fluvoxamine, Lescol and Ticlopidine were investigated through the structure-activity relationship approach. By means of a series of docking studies, the binding pockets of the two SNPs for the four compounds are explicitly defined that will be very useful for conducting mutagenesis studies, providing insights into personalization of drug treatments and stimulating novel strategies for finding desired personalized drugs.

An unambiguous assay for the cloned human sigma1 receptor reveals high affinity interactions with dopamine D4 receptor selective compounds and a distinct structure-affinity relationship for butyrophenones.

The ability of the sigma(1) receptor to interact with a huge range of drug structural classes coupled with its wide distribution in the body has contributed to it being implicated as a possible therapeutic target for a broad array of disorders ranging from substance abuse to depression to Alzheimer's disease. Surprisingly, the reported affinity values for some sigma(1) receptor ligands vary more than 50-fold. The potential of the sigma(1) receptor as a pharmacotherapeutic target prompted us to develop an unambiguous assay system for measuring the affinity of ligands to the cloned human sigma(1) receptor. In the course of characterizing this system and determining the true affinity values for almost three dozen compounds, it was discovered that some dopamine D(4) receptor selective compounds bind sigma(1) receptors with high affinity. A systematic analysis of haloperidol-like compounds revealed a clear structure-affinity relationship amongst clinically relevant butyrophenones. The antidepressant fluvoxamine, the drug of abuse methamphetamine, and the neurosteroid progesterone were amongst the many ligands whose interactions with the sigma(1) receptor were confirmed with our screening assay.

Use of isolated hepatocyte preparations for cytochrome P450 inhibition studies: comparison with microsomes for Ki determination.

Predicting drug-drug interactions requires an assessment of the drug concentration available to the enzyme active site, both in vivo, and within an in vitro incubation. These predictions are confounded when the inhibitor accumulates within the liver, either as a result of active transport processes or intracellular binding (including lysosomal trapping). In theory, hepatocytes should provide a more accurate estimation of inhibitory potency compared with microsomes for those compounds that undergo hepatic accumulation. However, they are not routinely used for Ki determination and there is limited comparative information available. Therefore, the aims of this study were to compare Ki values determined in rat microsomes and freshly isolated hepatocytes using six cytochrome P450 inhibitors (miconazole, fluconazole, ketoconazole, quinine, fluoxetine, and fluvoxamine) with a range of uptake properties (cell-to-medium concentration ratios 4.2-6000). Inhibition studies were performed using four probe substrates for CYP2C, CYP2D, and CYP3A enzymes (tolbutamide and phenytoin, dextromethorphan and midazolam, respectively). Comparison of unbound Ki values (range 0.05-30 microM) showed good agreement between microsomes and hepatocytes for inhibition of 18 pathways of metabolism. In addition to this, there was no relationship between the cell-to-medium concentration ratios (covering over 3 orders of magnitude) and the microsomal to hepatocyte Ki ratio of these inhibitors. These data suggest that the hepatic accumulation of these inhibitors results from intracellular binding rather than the involvement of uptake transporters and indicate that microsomes and hepatocytes appear to be equivalent for determining the inhibitory potency of the six inhibitors investigated in the present study.

High occupancy of sigma-1 receptors in the human brain after single oral administration of fluvoxamine: a positron emission tomography study using [11C]SA4503.

BACKGROUND: Sigma-1 receptors might be implicated in the pathophysiology of psychiatric diseases, as well as in the mechanisms of action of some selective serotonin reuptake inhibitors (SSRIs). Among the several SSRIs, fluvoxamine has the highest affinity for sigma-1 receptors (Ki = 36 nM), whereas paroxetine shows low affinity (Ki = 1893 nM). The present study was undertaken to examine whether fluvoxamine binds to sigma-1 receptors in living human brain. METHODS: A dynamic positron emission tomography (PET) data acquisition using the selective sigma-1 receptor ligand [(11)C]SA4503 was performed with arterial blood sampling to evaluate quantitatively the binding of [(11)C]SA4503 to sigma-1 receptors in 15 healthy male volunteers. Each subject had two PET scans before and after randomly receiving a single dose of either fluvoxamine (50, 100, 150, or 200 mg) or paroxetine (20 mg). The binding potential of [(11)C]SA4503 in 9 regions of the brain was calculated by a 2-tissue 3-compartment model. In addition, we examined the effects of functional polymorphisms of the sigma-1 receptor (SIGMAR1) gene on the binding potential of [(11)C]SA4503. RESULTS: Fluvoxamine bound to sigma-1 receptors in all brain regions in a dose-dependent manner, whereas paroxetine did not bind to sigma-1 receptors. However, there was no association between the SIGMAR1 gene polymorphism GC-241-240TT and binding potential. CONCLUSIONS: The study demonstrated that fluvoxamine bound to sigma-1 receptors in living human brain at therapeutic doses. These findings suggest that sigma-1 receptors may play an important role in the mechanism of action of fluvoxamine.

Identification of human cytochrome P450 enzymes involved in the major metabolic pathway of fluvoxamine.

The metabolism of fluvoxamine to fluvoxamino acid is known to involve a two-step oxidation process via an alcohol intermediate, fluvoxamino alcohol. The present study was carried out to identify the cytochrome P450 (CYP) enzyme(s) involved in the metabolism offluvoxamine to fluvoxamino alcohol using human liver microsomes and cDNA-expressed human CYP enzymes. The mean Km and Vmax values for the formation of fluvoxamino alcohol from fluvoxamine in human liver microsomes were 76.3 microM and 37.5 pmol min(-1) mg(-1) protein, respectively. The formation of fluvoxamino alcohol from fluvoxamine in pooled human liver microsomes was significantly inhibited by quinidine, a relatively specific CYP2D6 inhibitor, with a Ki value of 2.2 microM, whereas other several relatively specific CYP inhibitors did not inhibit the formation of fluvoxamino alcohol. In addition, only CYP2D6 of several cDNA-expressed human CYP enzymes examined showed substantial activity for the formation of fluvoxamino alcohol. Furthermore, the formation of fluvoxamino acid from fluvoxamino alcohol is potently inhibited by 4-methylpyrazole in human liver cytosol. These data suggest that CYP2D6 is the only enzyme predominantly responsible for the first-step oxidation of fluvoxamine to fluvoxamino alcohol, and alcohol dehydrogenase is involved in the second-step oxidation of fluvoxamino alcohol to the corresponding carbolic acid.