Venlafaxine Concentrations Research Articles

이팩사®XR서방캅셀(벤라팍신, 75 mg)에 대한 벤팍신®OR서방정의 생물학적동등성

To evaluate the bioequivalence of two venlafaxine formulations, a standard 2-way randomized cross-over study was conducted in twenty-four healthy male Korean volunteers. A single oral dose of 75 mg of test formulation Venfaxine (tablet) or reference formulation Efexor (capsule) was administered with one-week washout period. Plasma concentrations of venlafaxine were assayed for over a period of 72 hours with a well validated method using liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS). The . of maximum concentration and elimination half-life were ng/mL, h, and ng/mL, h for test and reference formulations, respectively. Time to reach maximum concentration expressed in median value (range), for the test and the reference, were 10 h (6-14) and 8h (4-12), respectively. Similarly, area under the plasma concentration-time curve, from time zero to last sampling time and from time zero to time infinity , for test and reference formulations were , and , , respectively. The parametric 90% confidence intervals on the mean of the differences between the two formulations (test-reference) of the log transformed values of , and were 0.9630 to 1.1383 and 0.8650 to 1.0446, respectively. The overall results indicate that the two formulations are bioequivalent and can be prescribe interchangeably.

Effect of Terbinafine and Voriconazole on the Pharmacokinetics of the Antidepressant Venlafaxine

This study investigated the effect of terbinafine and voriconazole on the pharmacokinetics of venlafaxine in healthy volunteers. Plasma concentrations of venlafaxine and O-desmethylvenlafaxine (ODV) were measured after ingestion of 75 mg venlafaxine without pretreatment (control), after terbinafine pretreatment, or after voriconazole pretreatment. During the terbinafine phase, the area under the plasma concentration-time curve (AUC(0-infinity)) of venlafaxine was on average 490% (P<0.001) and that of ODV 57% (P<0.001) of the corresponding control value. Terbinafine decreased the AUC(0-infinity) ratio of ODV over venlafaxine by 82% (P<0.001). Voriconazole slightly increased the sum of AUC(0-infinity) of venlafaxine plus AUC(0-infinity) of ODV (active moiety) by 31% (P<0.001). The most likely mechanism for the interaction between terbinafine and venlafaxine is the inhibition of CYP2D6-mediated O-demethylation of venlafaxine, whereas the minor effects of voriconazole are probably due to the inhibition of CYP3A4-, CYP2C9-, or CYP2C19-mediated metabolism of venlafaxine.

Venlafaxine in the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder

The objectives of this pilot study were to explore the changes in symptom severity, tolerability, and the pharmacodynamics of venlafaxine treatment in youths with attention-deficit/hyperactivity disorder (ADHD). This was a 2-week, open-label, outpatient trial of venlafaxine in children and adolescents, ages 5-17 years, with ADHD. Three dosing strata, 0.5, 1.0, and 2.0 mg/kg per day, were examined. ADHD symptom severity and improvement assessments included the ADHD Rating Scale (ARS-IV) and the Clinical Global Impressions Scale (CGI). During this study, venlafaxine, O-desmethylvenlafaxine (ODV), norepinephrine, and serotonin concentrations were obtained. Thirty-eight participants (33 males) were treated in this trial. Overall, parent-completed and teacher-completed ARS-IV total scores showed a statistically significant positive change at the end of the study when compared to baseline (p < 0.05). Significant increases in plasma venlafaxine concentrations were observed at day 15 when compared to day 8 (p = 0.04). In addition, plasma norepinephrine and serotonin concentrations were found to be significantly decreased from baseline at end of study (p < 0.05). Four patients ended participation in the study prematurely: lost to follow up (n = 2), withdrawal of consent (n = 1), and worsening of ADHD symptoms after 8 days of treatment (n = 1). There were no discontinuations due to other adverse events. Venlafaxine appeared to offer some benefit and appears to be relatively safe for the short-term treatment of ADHD in this open-label trial. The pharmacodynamics of venlafaxine in youths are consistent with serotonergic and neuradrenergic modulation.

Venlafaxine‐induced ecchymoses and impaired platelet aggregation

To describe a case of venlafaxine-induced ecchymoses. A patient with a history of ecchymoses coincident with venlafaxine therapy was rechallenged with the drug. Her platelet function was assessed with aggregation and ATP release studies before the rechallenge and after she developed ecchymoses. In addition, the effect of venlafaxine on platelet aggregation and ATP release was studied in vitro by adding the drug to platelet-rich plasma from normal donors. After 4 wk of treatment with venlafaxine our patient developed extensive ecchymoses. At that time her platelet aggregation and release responses to epinephrine, ADP, collagen, and arachidonic acid were markedly suppressed. Adding venlafaxine to normal platelet-rich plasma also dramatically reduced the aggregation and release responses to the same agonists as well as to serotonin, but the concentrations of venlafaxine required were 1000-fold greater than those normally achieved clinically. Our patient demonstrated an idiosyncratic hypersensitivity to the platelet inhibitory effects of venlafaxine. Because venlafaxine is an inhibitor of serotonin uptake by platelets and neurons, this mechanism may contribute to the impact of this drug on platelet function. However, our in vitro studies suggest that this hypothesis is inadequate to explain the observations completely.

CYP2D6 genotype and venlafaxine‐XR concentrations in depressed elderly

The elderly are at increased risk for medication-related adverse events. Recent reports indicate that venlafaxine may put the elderly at increased risk of cardio- and cerebrovascular adverse events. We investigated the relationship between the CYP2D6 polymorphism and steady-state plasma concentration of venlafaxine (VEN) and its primary metabolite o-desmethylvenlafaxine (ODV) in elderly participants receiving venlafaxine-XR for major depression in order to explore the contribution of pharmacogenetics to medication tolerability. Forty-six elderly participants received venlafaxine-XR for the treatment of major depression. CYP2D6 genotype and steady-state plasma levels of VEN and ODV were determined. Sixty-five percent of participants were homozygous of the wild type (WT) allele, whereas 35% carried one or more variant alleles associated with intermediate and poor 2D6 metabolizer status. VEN concentration per unit dose was significantly higher and ODV concentration per unit dose was significantly lower in participants who carried one or more variant alleles compared to participants who were homozygous for the WT allele. The VEN and ODV concentrations per unit dose were also correlated with creatinine clearance. CYP2D6 genotype was not associated with medication associated side-effects. Plasma dose-corrected concentrations of VEN and ODV correlated with genetically determined CYP2D6 enzymatic activity in depressed elders treated with venlafaxine-XR. This relationship was not masked by the effects of age-related illness or polypharmacy. Future clinical application of pharmacogenetics to examine 2D6-dependent medications may help reduce the incidence of medication adverse events particularly in those elders at higher risk for medication adverse events due to impaired renal or cardiac function.

Anesthesiologist Suicide with Atracurium

Atracurium is a nondepolarizing skeletal muscle relaxant used to facilitate endotracheal intubation and to induce skeletal muscle relaxation during surgery or mechanical ventilation. The drug undergoes a spontaneous non-enzymatic biotransformation, yielding laudanosine and an acrylate moiety. This report documents the case of a 45-year-old anesthesiologist who was found dead at the hospital where he worked. The victim was known to be depressed and undergoing treatment with venlafaxine. An empty syringe was found near the body. Toxicological analysis revealed the presence of laudanosine in the syringe, 0.6 mg/L of laudanosine in heart blood, 0.3 mg/L in urine, and 0.02 mg/L in vitreous humor. Meanwhile, concentrations of venlafaxine and O-desmethyl-venlafaxine, its active metabolite, were 0.7 and 1.1 mg/L in heart blood, 1.7 and 5.2 mg/L in urine, 0.5 and 0.7 mg/L in vitreous humor, and 400 and 20 mg in gastric content, respectively. All drugs and metabolites involved in the case were detected using gas chromatography with nitrogen-phosphorus detection (GC-NPD) and confirmed using GC-mass spectrometry in full scan mode after solid-phase extraction using Bond-Elut Certify columns. Additional high-performance liquid chromatography coupled to diode-array detection screening also obtained the same results. Quantitation of laudanosine and venlafaxine together with its metabolite was carried out using GC-NPD. No other drugs, including ethanol, were detected. Recoveries for laudanosine and venlafaxine were 89% and 86%, respectively, at 0.5 mg/L; intraday and interday precisions were 2% and 6%, and 3% and 7%, respectively; and limits of detection and quantitation were 6 and 20 ng/mL and 18 and 59 ng/mL, respectively. The linearity of the blood calibration curves was excellent for both drugs with r(2) values of > 0.999 (range 0.1-2.0 mg/L). Based on the autopsy findings, case history, and toxicology results, the forensic pathologists ruled that the cause of death was an overdose of atracurium, and the manner of death was suicide.

Open‐Field Behavioural Alterations in Liver‐Impaired and Sham‐Operated Rats after Acute Exposure to the Antidepressant Venlafaxine

Patients with chronic liver impairment often display symptoms of affective psychiatric nature where the choice for antidepressant treatment is rational. Since caution is recommended when these drugs are used in such patients, a dose reduction is usually performed. We have previously reported that a dose reduction to liver-impaired portacaval shunted rats has resulted in similar brain concentrations of venlafaxine as compared to sham-operated control rats that received a two times higher dose. The main aim of the present study was therefore to investigate if this "normalisation" in pharmacokinetics of the portacaval-shunted rats also was true for the pharmacodynamic response in terms of drug effect on spontaneous open-field behaviour. Thus, portacaval-shunted rats received a single reduced dose (5 mg/kg) of venlafaxine or saline, whereas sham-operated rats received either 10 mg/kg or saline. Thereafter, central and peripheral arena locomotor and rearing activities were recorded during 60 min. The venlafaxine-treated portacaval-shunted and sham rats displayed reduced and unchanged overall behavioural activities compared with corresponding controls, respectively. However, the ratios between centrally and peripherally performed behavioural activities were higher in the venlafaxine-treated sham rats, indicating an increase in central arena activity as compared to the sham-saline and portacaval-shunted rats. The present study indicates that, despite a 50% dose reduction, caution still is necessary when antidepressants are used in liver insufficient subjects. This study also shows the importance of detailed open-field behavioural studies in which both central and peripheral activities are recorded for measurement of open-field behavioural drug effects.

An open-label, randomized, crossover study of the relative bioavailability of desvenlafaxine after oral administration of extended-release venlafaxine and sustained-release desvenlafaxine succinate in healthy subjects

Background/Aims To assess the relative bioavailability of desvenlafaxine (DV) after single oral doses of extended-release venlafaxine (VEN-ER) and sustained-release desvenlafaxine succinate (DVS-SR) in healthy subjects. Methods A randomized single-dose crossover study was conducted with 35 healthy male and female subjects. The 4 oral doses were 75 and 150 mg of VEN-ER and 75 and 150 mg of DVS-SR given after a medium-fat breakfast. Routine laboratory tests, vital signs, and electrocardiograms (ECG) were measured throughout the study. A 100-mm Visual Analog Scale (VAS) for nausea was used to evaluate the profile for nausea during treatment periods. The maximum nausea experienced (Emax) was calculated. Plasma concentrations of venlafaxine (VEN) and DV were analyzed by model-independent methods. Results DV was well absorbed with higher values for Cmax and AUC after administration of DVS-SR in comparison with VEN-ER. There was a statistically significant difference in nausea intensity between DVS-SR and VEN-ER. Mean VAS Emax values for DVS-SR were approximately 6-fold lower for the 75 mg doses and 2-fold lower for the 150 mg doses compared with the same doses of VEN-ER. Conclusion DVS-SR provided good absorption and drug availability to the systemic circulation with DV plasma concentrations higher than those obtained after similar doses of VEN-ER. Nausea was less severe with DVS-SR than with VEN-ER. Clinical Pharmacology & Therapeutics (2005) 77, P86–P86; doi: 10.1016/j.clpt.2004.12.222

High-dose venlafaxine treatment in a depressed patient with a genetic CYP2D6 deficiency

A female patient (47 years) who suffered from a severe episode of a recurrent depression with psychotic symptoms (F33.3) firstly underwent several unsuccessful treatments. She was then submitted to a combined treatment with 2×300 mg/day extended-release venlafaxine (VEN) and lithium (0.7 mmol/l). She responded within 7 weeks and, after 9 weeks, she showed full remission. Moreover, she tolerated this medication well. Steady-state plasma concentrations of VEN and its metabolites and their enantiomers were measured. The concentrations of VEN and its metabolite O-demethyl-VEN (ODV) were 1024 and 234 ng/ml, respectively. The unusually high concentration of the parent compound in comparison to the metabolite is mainly explained by an impaired metabolism of R-VEN in this patient, who by genotyping was shown to have a genetic deficiency of CYP2D6. In conclusion, in patients suffering from non-response to an antidepressant treatment, an individualised treatment strategy should be developed, and stereoselective therapeutic drug monitoring and genotyping may be recommended.

Differential enhancement of antidepressant penetration into the brain in mice with abcb1ab (mdr1ab) P-Glycoprotein gene disruption

Background Mice with a genetic disruption (knockout) of the multiple drug resistance (abcb1ab) gene were used to examine the effect of the absence of the drug-transporting P-glycoprotein (P-gp) at the blood–brain barrier on the uptake of the antidepressants venlafaxine, paroxetine, mirtazapine, and doxepin and its metabolites into the brain. Methods One hour after subcutaneous injection of venlafaxine, paroxetine, mirtazapine, or doxepin, knockout and wildtype mice were sacrificed, and the drug concentrations in brain, spleen, kidney, liver, and plasma were measured. Results The cerebrum concentrations of doxepin, venlafaxine, and paroxetine were higher in knockout mice, demonstrating that these substances are substrates of P-gp and that abcb1ab activity at the level of the blood–brain barrier reduces the penetration of these substances into the brain. In contrast, brain distribution of mirtazapine was indistinguishable between the groups. Conclusions The differences reported here in brain penetration of antidepressant drugs that depend on the presence of the abcb1ab gene may offer an explanation for poor or nonresponse to antidepressant treatment. Furthermore, they may be able to explain in part the discrepancies between plasma levels of an antidepressant and its clinical effects and side effects.

Melperone is an inhibitor of the CYP2D6 catalyzed O-demethylation of venlafaxine.

Melperone, a butyrophenone neuroleptic, is frequently used for its sleep-inducing properties. Despite its common use for more than 30 years, it is not yet characterized regarding its effects on cytochrome P450 s (CYPs). In an open pilot study, effects of melperone on the steady-state blood levels of venlafaxine, a recently introduced serotonin- and noradrenaline reuptake inhibiting antidepressant, were assessed. The dose-corrected serum concentrations of venlafaxine and O-desmethylvenlafaxine were analyzed retrospectively in a therapeutic drug-monitoring (TDM) database comprising 94 patients. In addition, three patients received venlafaxine and melperone concomitantly and the serum concentrations of venlafaxine and O-desmethylvenlafaxine were analyzed before, during, and after melperone co-medication. The effect of melperone on CYP2D6 was further assessed in seven patients by means of the dextromethorphan O-demethylation, which serves as a CYP2D6 probe reaction. Patients treated concomitantly with venlafaxine and melperone had significantly higher (mean +/- SD) venlafaxine (3.27 +/- 2.9 vs. 0.97 +/- 0.99 ng/ml per mg/d; p < 0.05) and lower O-desmethylvenlafaxine serum concentrations (0.69 +/- 0.35 vs. 1.51 +/- 0.9 ng/ml per mg/d; p < 0.01) compared to patients without melperone comedication. In the three patients, venlafaxine serum concentrations increased, on average by 52 % during melperone co-medication, whereas O-desmethylvenlafaxine was decreased, on average by 29 %. Administration of melperone over three days elevated the ratio of dextromethorphan to dextrorphan from 0.044 +/- 0.04 to 0.09 +/- 0.083 (p < 0.05). This study pointed to an inhibitory effect of melperone on the O-demethylation of venlafaxine. Because the O-demethylation of venlafaxine is almost exclusively catalyzed by CYP2D6 it is concluded that melperone is an inhibitor of CYP2D6. The hypothesis was further corroborated by the inhibitory effect of melperone on the dextromethorphan O-demethylation.

Effects on drug disposition, brain monoamines and behavior after chronic treatment with the antidepressant venlafaxine in rats with experimental hepatic encephalopathy

Patients with chronic hepatic encephalopathy (HE) may present affective symptoms and antidepressant drug treatment in this condition is not uncommon. The present microdialysis study investigated treatment with the chronic antidepressant venlafaxine (VEN) in experimental HE with regard to tentative changes in pharmacokinetic and/or pharmacodynamic parameters. Three weeks after portacaval shunt (PCS) or sham operation in rats, VEN (10 mg/kg daily) was administered by implanted osmotic minipumps. VEN treatment for 14 days resulted in higher concentrations of VEN in PCS rats than in sham controls in serum and brain compartments, and the VEN levels in serum and brain were strongly inter-correlated. The serum N-desmethylvenlafaxine concentration did not differ between the groups, but correlated with the serum VEN levels. The other VEN metabolites were below the quantification limits. VEN treatment for 9–12 days significantly stimulated locomotion and rearing in the open field in sham controls, but failed to do so in the PCS rats. The concentrations of noradrenaline, dopamine, 5-HT, and 5-HIAA in neocortical dialysates were higher in PCS than in sham rats after 14 days of VEN treatment, but the elevations reached statistical significance only in the case of dopamine and 5-HIAA. In summary, there were significant pharmacokinetic and pharmacodynamic alterations in rats with experimental HE as compared to controls. The described experimental HE model may be useful for continued pharmacokinetic/pharmacodynamic interaction studies to unravel the pathophysiological consequences of HE on the CNS.

Venlafaxine in neuropathic pain following treatment of breast cancer

Amitriptyline effectively relieves neuropathic pain following treatment of breast cancer. However, adverse effects are a major problem. Venlafaxine has no anticholinergic effects and could have a better compliance. The aim of the study was to evaluate the effectiveness of venlafaxine in neuropathic pain. The study was a randomized, double-blind, crossover comparison of venlafaxine and inactive placebo. The study lasted 10 weeks. The number of tablets (18.75mg) taken daily was increased by one at a 1 week interval. Pain intensity and pain relief were registered daily by a diary and by a questionnaire and a computer program (Painscreen™) on each visit. Adverse effects were evaluated with the diaries and a 10-item list on each visit. Also, anxiety and depression were measured on each visit. Venous blood samples were collected before the treatment and at 4 weeks for the determination of the serum levels of venlafaxine and its three metabolites. Thirteen patients were analysed. The average daily pain intensity as reported in the diary (primary outcome) was not significantly reduced by venlafaxine compared with placebo. However, the average pain relief (diary) and the maximum pain intensity (retrospective assessment by the computer program) were significantly lower with venlafaxine compared with placebo. Anxiety and depression were not affected. Adverse effects did not show significant differences between treatments. The two poor responders had low venlafaxine concentrations whereas the two slow hydroxylizers had high venlafaxine concentrations and excellent pain relief. Thus, higher doses could be used in order to improve pain relief.

Effect of halving the dose of venlafaxine to adjust for putative pharmacokinetic and pharmacodynamic changes in an animal model of chronic hepatic encephalopathy.

Patients with chronic hepatic encephalopathy display monoaminergic perturbations together with affective symptoms. Thus, these patients belong to a group with a probability of receiving antidepressant drug treatment. The liver impairment may result in pharmacokinetic alterations of the antidepressant drug, which in turn may affect the already perturbed monoaminergic function. Venlafaxine (VEN) was administered as a single subcutaneous challenge to portacaval shunted (experimental hepatic encephalopathy model) rats (5 mg/kg) and sham-operated rats (5 and 10 mg/kg). The aims were to investigate whether a reduced dose in portacaval shunted rats resulted in higher concentrations of VEN and serotonin as compared to control rats, which had been demonstrated earlier when the rats received the same dose (10 mg/kg). A 50% reduction of the dose of VEN administered to portacaval shunted rats resulted in elevated levels of VEN in serum, brain parenchyma, and brain dialysate about 300 minutes after the injection. The VEN challenge increased the serotonin and noradrenaline concentrations in dialysate in portacaval shunted rats and both sham groups, but the three VEN groups did not differ in any major way in serotonin and noradrenaline output. Therefore, when the dose of VEN administered to experimental hepatic encephalopathy was reduced 50% as compared to control rats, mainly pharmacokinetic, and possibly also monoaminergic, alterations were observed.

Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans.

CYP2D6 is the major enzyme involved in the metabolism of venlafaxine. Subjects with a low CYP2D6 activity have increased plasma concentrations of venlafaxine that may predispose them to cardiovascular side effects. In vitro and in vivo studies showed that diphenhydramine, a nonprescription antihistamine, can inhibit CYP2D6 activity. Therefore, the authors investigated in this study a potential drug interaction between diphenhydramine and venlafaxine. Fifteen male volunteers, nine with the extensive metabolizer (EM) and six with the poor metabolizer (PM) phenotype of CYP2D6, received venlafaxine hydrochloride 18.75 mg orally every 12 hours for 48 hours on two occasions (1 week apart): once alone and once during the concomitant administration of diphenhydramine hydrochloride (50 mg every 12 hours). Blood and urine samples were collected for 12 hours under steady-state conditions. In EMs, diphenhydramine decreased venlafaxine oral clearance from 104+/-60 L/hr to 43+/-23 L/hr (mean +/- SD; p < 0.05) without any effect on renal clearance (4+/-1 L/hr during venlafaxine alone and 4+/-2 L/hr during venlafaxine plus diphenhydramine). In PMs, coadministration of diphenhydramine did not cause significant changes in oral clearance and partial metabolic clearances of venlafaxine to its various metabolites. Diphenhydramine disposition was only slightly affected by genetically determined low CYP2D6 activity or concomitant administration of venlafaxine. In conclusion, diphenhydramine, at therapeutic doses, inhibits CYP2D6-mediated metabolism of venlafaxine in humans. Clinically significant interactions could be encountered during the concomitant administration of diphenhydramine and other antidepressant or antipsychotic drugs that are substrates of CYP2D6.

Sustained administration of the antidepressant venlafaxine in rats: pharmacokinetic and pharmacodynamic findings.

Rats were administered venlafaxine (10 mg/kg per day) for 14 days by using subcutaneously implanted osmotic minipumps. The present study assessed the distribution of VEN in different compartments, whether the VEN concentration in the compartments correlated, the effect of VEN on dialysate monoamine levels and on the spontaneous open-field behavior, and possible relations between the pharmacokinetic and pharmacodynamic parameters. The venlafaxine level in serum after sustained treatment was about 25% of the concentration in brain parenchyma and much higher than in brain dialysate. There was a clear correlation between venlafaxine concentrations in blood and brain compartments. The sustained venlafaxine challenge resulted in higher neocortical concentration of serotonin and noradrenaline, lower 5-hydroxyindole-3-acetic acid levels and increased locomotor activity in the central part of the test arena as compared to controls. No correlations were found between the venlafaxine concentration and brain monoamine parameters or the open-field behaviors. We conclude that, although species differences in pharmacokinetic properties for venlafaxine between rat and man exist, the pharmacokinetic correlations found after sustained treatment add information to the in vivo nature of the drug. Also, more studies like the present need to be performed to find the pharmacokinetic/pharmacodynamic interrelations for drugs like VEN.

The impact of the CYP2D6 and CYP2C19 genotypes on venlafaxine pharmacokinetics in a Japanese population

The cytochrome P450 isozymes CYP2D6 and CYP2C19 exhibit genetic polymorphism in human, including a marked interethnic difference. As the functional status of the isozymes CYP2D6 and CYP2C19 have an impact on the pharmacokinetics of some antidepressants, we investigated whether the disposition of venlafaxine was affected by the CYP2D6 and CYP2C19 genotypes. Twenty-eight adult Japanese men in good health participated in this study. Genomic DNA was isolated from peripheral lymphocytes, and the CYP2D6 genotype was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and XbaI-RFLP analysis. Subjects were categorized into the following four groups: group 1 CYP2D6*10/*10; group 2 CYP2D6*1/*10 and *2/*10; group 3 CYP2D6*1/*1, *1/*2 and *2/*2; and group 4 the other genotypes. Two defective CYP2C19 alleles (CYP2C19*2 and CYP2C19*3) were identified by means of PCR-RFLP analysis. Venlafaxine was administered orally following an overnight fast. Plasma concentrations of venlafaxine and O-desmethylvenlafaxine were monitored using high-performance liquid chromatography up to 24 h. The peak plasma concentration and values of area under the concentration-time curve up to 24 h for venlafaxine were 298% and 453% higher for group 1 than group 3, and 91% and 120% higher for group 2 than for group 3, respectively. The homozygote for two defective alleles of CYP2C19 showed a higher concentration of venlafaxine within group 1 and group 2. The CYP2D6*10 allele and two CYP2C19 defective alleles, common in an Asian population, are the most likely genetic factors to use in determining interindividual differences in the pharmacokinetics of venlafaxine, although the results with respect to CYP2C19 are preliminary because of the few subjects used.

Relationship between clinical effects, serum drug concentration, and concurrent drug interactions in depressed patients treated with citalopram, fluoxetine, clomipramine, paroxetine or venlafaxine.

The relationship between clinical effects and plasma concentrations of citalopram, fluoxetine, clomipramine, paroxetine and venlafaxine was studied in 119 cases of major depression. Clinical effects were evaluated using the Clinical Global Impression (CGI) improvement scale. Antidepressants were quantified by a separative chromatographic methodology. Plasma concentrations in responder patients were compared with the plasma concentrations proposed in literature as effective values. We found that the usual therapeutic window is convenient for citalopram and clomipramine, but could be reduced for fluoxetine and increased for venlafaxine and paroxetine. Concurrent drug interactions were also evaluated and clomipramine or citalopram plasma levels were found to be influenced by the presence of associated drugs. A larger study is needed, taking into account not only plasma concentrations and clinical effects, but also some pharmacokinetic data, especially the metabolic activity characterising the patient, and the presence or not of associated drugs. Copyright 2000 John Wiley & Sons, Ltd.

Effect of the CYP2D6*10 genotype on venlafaxine pharmacokinetics in healthy adult volunteers.

Interindividual differences in the pharmacokinetics of venlafaxine, a new antidepressant, were shown during early clinical trials in Japan. Venlafaxine is metabolized mainly by CYP2D6 to an active metabolite, O-desmethylvenlafaxine (ODV). Therefore, the influence of the CYP2D6 genotypes on venlafaxine pharmacokinetics was examined in a Japanese population. Twelve adult Japanese men in good health participated in this study. Genomic DNA was isolated from peripheral lymphocytes, and the CYP2D6 genotypes were determined by codon 188C/T, 1934G/A, 2938G/A and 4268G/C mutations using endonuclease tests based on PCR and by Xba I-RFLP analysis. Subjects were categorized into the following 3 groups (n=4 in each group); Group1: CYP2D6*10/*10, *5/*10, Group2: CYP2D6*1/*10, *2/*10 and Group3: CYP2D6*1/*1, CYP2D6*1/*2. Venlafaxine (25 mg, n=6; 37.5 mg, n=6) was administered orally at 09.00 h following an overnight fast. Plasma concentrations of venlafaxine and ODV were monitored by h.p.l.c. for 48 h. The Cmax and AUC of venlafaxine were 184% and 484% higher in the group 1 subjects than in the group 3 subjects, and 101% and 203% higher in the group 1 than in the group 2, respectively. These results suggest that CYP2D6*10 influences the pharmacokinetics of venlafaxine in a Japanese population.

A Study Involving Venlafaxine Overdoses: Comparison of Fatal and Therapeutic Concentrations in Postmortem Specimens

The distribution and redistribution of venlafaxine were investigated in two overdoses and several cases involving the therapeutic use of venlafaxine. Blood, liver, bile vitreous humor, urine and gastric contents were analyzed using high performance liquid chromatography with ultraviolet detection. Blood concentrations of venlafaxine in the two overdose cases were 53 mg/L and 78 mg/L. Comparison of venlafaxine concentrations in blood samples taken at different times after death revealed increases in concentrations over time, suggesting the possible postmortem redistribution of venlafaxine.