Verlängerung der QT-Zeit
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Für die Kombination von Cimetidin und Moclobemid liegen uns keine zusätzlichen Warnhinweise vor. Bitte konsultieren Sie zusätzlich die jeweiligen Fachinformationen.
|Moclobemid||1.53 [0.92,3.91] 1||1.53|
Die genannten Expositionsveränderungen beziehen sich jeweils auf Veränderungen der Plasmakonzentrations-Zeit-Kurve [ AUC ]. Eine Veränderung der Exposition von Cimetidin haben wir nicht erkannt. Den Einfluss von Moclobemid können wir aktuell nicht abschätzen. Die Exposition von Moclobemid erhöht sich auf 153%, wenn eine Kombination mit Cimetidin (153%) erfolgt. Die AUC liegt dabei je nach CYP2C19
Für die Berechnung der individuellen Expositionsveränderungen durch die Wechselwirkungen werden als Ausgangsbasis die pharmakokinetischen Parameter der durchschnittlichen Population verwendet.
Cimetidin hat eine mittlere orale Bioverfügbarkeit [ F ] von 65%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell verändern. Die terminale Halbwertszeit [ t12 ] ist mit 1.6333333 Stunden eher kurz und konstante Plasmaspiegel [ Css ] werden schnell erreicht. Die Proteinbindung [ Pb ] ist mit 19% sehr schwach und das Verteilungsvolumen [ Vd ] ist mit 91 Liter sehr gross. Die Metabolisierung erfolgt nicht über die gängigen Cytochrome und der aktive Transport erfolgt zum Teil über BCRP und PGP. Unter anderem ist Cimetidin ein Hemmer von CYP2C19.
Moclobemid hat eine mittlere orale Bioverfügbarkeit [ F ] von 54%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell verändern. Die terminale Halbwertszeit [ t12 ] ist mit 1.64 Stunden eher kurz und konstante Plasmaspiegel [ Css ] werden schnell erreicht. Die Proteinbindung [ Pb ] ist mit 50% eher schwach und das Verteilungsvolumen [ Vd ] ist mit 95 Liter sehr gross. weshalb bei einer mittleren hepatische Extraktionsrate von 0.45 sowohl der Leberblutfluss [ Q ] als auch eine Veränderung der Proteinbindung [ Pb ] relevant sind. Die Metabolisierung findet vor allem über CYP2C19 statt.
|Serotonerge Effekte a||3||Ø||+++|
Das Risiko für ein serotonerges Syndrom ist erhöht, aber ohne exakte
Bewertung: Moclobemid erhöht die serotonerge Aktivität stark. Gemäss unseren Erkenntnissen erhöht Cimetidin nicht die serotonerge Aktivität.
|Kiesel & Durán b||2||+||+|
Empfehlung: Insbesondere nach einer Dosiserhöhung und bei Dosierungen im oberen therapeutischen Bereich sollte vorsichtshalber auf anticholinerge Symptome geachtet werden.
Bewertung: Cimetidin und Moclobemid beeinflussen das anticholinerge System nur mild. Das Risiko für ein anticholinerge Syndrom ist bei dieser Medikation eher als gering einzustufen, wenn die Dosierung sich im üblichen Bereich befindet.
Verlängerung der QT-Zeit
Bewertung: In Kombination können Cimetidin und Moclobemid potentiell ventrikuläre Arrhythmien vom Typ Torsades de pointes auslösen.
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Abstract: Moclobemide is a reversible and selective inhibitor of the enzyme monoamine oxidase (MAO) subtype A with a broad spectrum of antidepressant activity. Controlled clinical studies suggest that the short term clinical efficacy of moclobemide is significantly superior to that of placebo, and comparable to that of the tricyclic antidepressants clomipramine, amitriptyline, imipramine and desipramine, the irreversible MAO inhibitor tranylcypromine and the second-generation antidepressants maprotiline, mianserin and fluvoxamine in the treatment of major depressive illness. Moclobemide appears to be equally effective in endogenous and nonendogenous depression, producing marked amelioration of clinical features of psychomotor retardation and depressed mood. Moclobemide is well tolerated, being largely devoid of the anticholinergic adverse effects, symptomatic postural hypotension and weight gain variously associated with the tricyclic antidepressants and irreversible MAO inhibitors, and appears considerably safer on overdosage than the tricyclic and second generation antidepressants. Moreover, moclobemide offers the advantage over the older, irreversible MAO inhibitors of causing only minimal potentiation of the pressor response to dietary tyramine (the so-called 'cheese effect'). Consequently, the risk of potentially fatal hypertensive crisis, a major deterrent to the wider acceptance of these earlier compounds, is substantially reduced with moclobemide, and the need for dietary precautions is minimised. With its efficacy against endogenous and nonendogenous depression, relatively rapid onset of antidepressant activity, and absence of carry-over effects on treatment withdrawal, moclobemide is likely to make an important contribution to the treatment of major depressive illness. Its favourable tolerability profile, safety on overdosage and beneficial effect on age-related cognitive impairment may be of particular value in the elderly and those with concurrent physical illness.
Abstract: The influence of cimetidine on the absorption and disposition of moclobemide was examined in eight healthy male subjects. A single 100 mg intravenous and 100 mg oral dose of moclobemide was administered before and after 2 weeks of cimetidine administration (200 mg five times a day). The data on intravenous administration indicated that cimetidine produced a statistically significant alteration in the following disposition parameters (mean values for control versus cimetidine): systemic clearance, 46.6 versus 28.3 L/hr; mean residence time, 2.1 versus 3.2 hours; elimination half-life, 1.6 versus 2.3 hours. There was no significant difference in the steady-state volume of distribution. The absolute oral bioavailability of moclobemide increased significantly after cimetidine administration (54% versus 68%), as did the maximum plasma concentration after a single oral dose (575 versus 787 ng/ml). There were no differences in the mean absorption time or time to achieve maximum concentration. The values of systemic and apparent oral clearances of moclobemide after cimetidine administration were directly related to the corresponding control values before cimetidine. In contrast, the percentage change in clearance was essentially independent of the corresponding initial control clearance value.
Abstract: This study was undertaken to determine the absolute bioavailability and steady-state concentrations of moclobemide after doses of 150 mg. In 14 healthy human volunteers, no differences in tmax, t 1/2 beta, C1/F, Cmax and AUC were found between a single oral dose of 100 mg and one of 150 mg. The mean absolute oral availability was 0.66 and 0.69 respectively. Plasma concentration profiles of moclobemide on repeated dosing with 150 mg 3 times daily for 15 days were essentially superimposable, although the mean concentration was higher than after the single 150 mg dose. This concentration increased over the first week and then remained relatively constant. Mean accumulation factors for moclobemide during the first week were 1.85 for Cmax and 3.0 for AUC. These values were higher than predicted from single-dose characteristics. There was a marked reduction in the variability of AUC and clearance (C1/F) values at steady-state compared with the first dose. Minimum plasma concentrations of the 2 metabolites, Ro 12-5637 and Ro 12-8095, were relatively stable throughout dosing. The exact mechanism of the decrease in systemic and oral clearance of moclobemide with time during multiple oral dosing is not known at present. Either moclobemide inhibits its own clearance or moclobemide metabolism is inhibited by one or more of its metabolites. The findings indicate that, if dosage needs to be adjusted during treatment with moclobemide, the changes should be made carefully and at intervals of not less than 1 week.
Abstract: The absorption and disposition kinetics of moclobemide (Ro 11-1163), a new reversible and preferential monoamine oxidase-A enzyme inhibitor, were examined in 12 normal male subjects. An intravenous infusion was administered before and after a 15-day multiple oral dosing regimen (100 mg t.i.d.). Plasma concentration-time data were obtained after each intravenous infusion, after the first oral dose, during two dosing intervals at steady state, and before the second daily dose on several days. The disposition values (percent coefficient of variation in parentheses) after the first and second intravenous infusions, respectively, were: clearance, 39.4 (15%) and 29.1 (12%) L/hr; elimination half-life, 1.60 (15%) and 2.00 (18%) hours; and volume of distribution at steady state, 84.3 (11%) and 80.7 (15%) L. The absolute oral bioavailability increased from 0.56 after the first oral dose to 0.86 and 0.90 after the first and second weeks of administration, respectively. The reduced metabolic, presumably hepatic, clearance may be the result of self-inhibition or metabolite inhibition of moclobemide clearance.
Abstract: The pharmacokinetic variability of moclobemide, a new short half-life reversible selective inhibitor of monoamine oxidase (MAO) was investigated through analysis of concentrations measured during early open clinical use. Eighty-nine depressed patients, aged 21-96 years, were included in the present study. Doses ranged from 200 to 900 mg/day, and the time interval between blood sampling and last drug intake on the previous day was between 8 and 23 h. Intraindividual variability was generally moderate, with a few patients displaying consistently high concentrations despite moderate doses. Interindividual variability for measured concentrations was approximately 300-fold. After concentration decrease with time was taken into account (average half-life estimate of 4.6 h), age was identified as a major factor responsible for between-patient variability. Average concentration increase per decade of age was 38%. Neither gender, weight, height, smoking, nor alcohol intake explained a significant additional part of the variance. Analysis of residuals also suggested that phenytoin co-medication may induce moclobemide metabolism. The present study indicates that concentration monitoring of a newly marketed drug can contribute to gaining insight into its pharmacokinetic behavior and to enhancing its rational use in clinical practice.
Abstract: No Abstract available
Abstract: No Abstract available
Abstract: Recently, the use of astemizole and terfenadine, both non-sedating H1-antihistamines, caused considerable concern. Several case reports suggested an association of both drugs with an increased risk of torsades de pointes, a special form of ventricular tachycardia. The increased risk of both H1-antihistamines was associated with exposure to supratherapeutic doses; for terfenadine the risk was also associated with concomitant exposure to the cytochrome P-450 inhibitors ketoconazole, erythromycin and cimetidine. To predict the size of the population that runs the risk of developing this potentially fatal adverse reaction in the Netherlands, the prevalence of prescribing supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was studied. Data were obtained from the PHARMO data base in 1990, a pharmacy-based record linkage system encompassing a catchment population of 300,000 individuals. The results of the study showed that the prescribing of supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was low. Furthermore, the results of a sensitivity analysis showed that the risk of fatal torsades de pointes has to be as high as 1 in 10,000 to cause one death in the Netherlands in one year.
Abstract: No Abstract available
Abstract: There has been a resurgence of interest in the use of monoamine oxidase (MAO) enzyme inhibitors for the treatment of depression. Unlike the first-generation MAO inhibitors, the current drugs are readily reversible in their action, resulting in far less concern about interactions with certain foods and drugs which could lead to serious pressor effects. Furthermore, the current drugs are far more selective in their actions as a result of the ability to affect either the MAO-A or the MAO-B isoenzyme. Moclobemide is an example of a reversible MAO-A inhibitor which has been extensively studied and whose pharmacokinetic, clinical pharmacological and toxicological profiles have been thoroughly defined. Moclobemide has a short disposition half-life and intermediate values for systemic clearance and volume of distribution; half-life increases somewhat with dose. The drug is completely metabolised by the liver. Moclobemide is rapidly and completely absorbed following oral administration in a variety of dosages and forms. The drug has a high intrinsic (apparent oral) clearance which results in a substantial hepatic first-pass effect and, while there is marked interindividual variation, differences within an individual are small. A time- and dose-dependence is observed with multiple oral administration: clearance decreases with administration during the first week and thereafter remains constant. The exact mechanism of this effect is not known, but it may reflect inhibition of elimination by metabolites (the kinetics may always be described as being first-order). Moclobemide disposition is not affected by renal disease, nor is there substantial alteration with advanced age. Liver disease causes a dramatic reduction in clearance; dosage must be adjusted for patients with liver disease. There is minimal transfer of the drug into breast milk, such that breast-feeding neonates are exposed to only a very small dose of the drug. Moclobemide administration results in a minimal interaction with exogenous amines (e.g. tyramine and pressor amine drugs); the so-called 'cheese effect' is therefore of little concern. As a result, the drug has an excellent tolerability profile both within the therapeutic dose range and in overdose (no deaths have been attributed to moclobemide intoxication per se). Cimetidine inhibits the elimination of moclobemide. Moclobemide appears to affect several isoenzymes of the cytochrome P450 (CYP) system (CYP2C19, CYP2D6 and CYP1A2). The adverse events profile of moclobemide indicates only mild and transient effects at a relatively low rate of occurrence.
Abstract: 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.
Abstract: No Abstract available
Abstract: Astemizole (Hismanal), an antihistamine agent, has been reported to be associated with ventricular arrhythmias. In this paper we present a case of QT prolongation and torsades de pointes (TdP) in a 77-year-old woman who had been taking astemizole (10 mg/day) for 6 months because of allergic skin disease. At the time of admission, the serum concentration of astemizole and its metabolites was markedly elevated at 15.85 ng/ml, approximately 3 times the normal level. The patient was also taking cimetidine, a known inhibitor of cytochrome P-450 enzymatic activity, and during her admission was diagnosed as having vasospastic angina. To the best of our knowledge, this is the first report of astemizole-induced QT prolongation and TdP in Japan.
Abstract: BACKGROUND: Moclobemide, an antidepressant with selective monoamine oxidase-A inhibitory action, is known to be metabolized by CYP2C19 and is also reported to be an inhibitor of CYP2C19, CYP2D6, and CYP1A2. To confirm the involvement of CYP2C19, we performed a pharmacokinetic interaction study. METHODS: The effect of omeprazole on the pharmacokinetics of moclobemide was studied in 16 healthy volunteers. The volunteer group comprised 8 extensive metabolizers and 8 poor metabolizers of CYP2C19, which was confirmed by genotyping. Subjects were randomly allocated into two sequence groups, and a single-blind, placebo-controlled, two-period crossover study was performed. In study I, a placebo was orally administered for 7 days. On the eighth morning, 300 mg of moclobemide and 40 mg of placebo were coadministered with 200 mL of water, and a pharmacokinetic study was performed. During study II, 40 mg of omeprazole was given each morning instead of placebo, and pharmacokinetic studies were performed on the first and eighth day with 300 mg of moclobemide coadministration. RESULTS: The inhibition of moclobemide metabolism was significant in extensive metabolizers even after a single dose of omeprazole. After daily administration of omeprazole for 1 week, the pharmacokinetic parameters of moclobemide and its metabolites in extensive metabolizers changed to values similar to those in poor metabolizers. In poor metabolizers, no remarkable changes in the pharmacokinetic parameters were observed. CONCLUSION: Our results show that CYP2C19 is an important enzyme in the elimination of moclobemide and that it is extensively inhibited by omeprazole in extensive metabolizers, but not in poor metabolizers.
Abstract: Renal drug interactions can result from competitive inhibition between drugs that undergo extensive renal tubular secretion by transporters such as P-glycoprotein (P-gp). The purpose of this study was to evaluate the effect of itraconazole, a known P-gp inhibitor, on the renal tubular secretion of cimetidine in healthy volunteers who received intravenous cimetidine alone and following 3 days of oral itraconazole (400 mg/day) administration. Glomerular filtration rate (GFR) was measured continuously during each study visit using iothalamate clearance. Iothalamate, cimetidine, and itraconazole concentrations in plasma and urine were determined using high-performance liquid chromatography/ultraviolet (HPLC/UV) methods. Renal tubular secretion (CL(sec)) of cimetidine was calculated as the difference between renal clearance (CL(r)) and GFR (CL(ioth)) on days 1 and 5. Cimetidine pharmacokinetic estimates were obtained for total clearance (CL(T)), volume of distribution (Vd), elimination rate constant (K(el)), area under the plasma concentration-time curve (AUC(0-240 min)), and average plasma concentration (Cp(ave)) before and after itraconazole administration. Plasma itraconazole concentrations following oral dosing ranged from 0.41 to 0.92 microg/mL. The cimetidine AUC(0-240 min) increased by 25% (p < 0.01) following itraconazole administration. The GFR and Vd remained unchanged, but significant reductions in CL(T) (655 vs. 486 mL/min, p < 0.001) and CL(sec) (410 vs. 311 mL/min, p = 0.001) were observed. The increased systemic exposure of cimetidine during coadministration with itraconazole was likely due to inhibition of P-gp-mediated renal tubular secretion. Further evaluation of renal P-gp-modulating drugs such as itraconazole that may alter the renal excretion of coadministered drugs is warranted.
Abstract: BACKGROUND: Several medications have been found to prolong the QT interval in overdose. This can predispose to torsade de pointes-type ventricular tachycardia. AIMS: To analyse the effects of moclobemide deliberate self-poisoning on the length of both QT and corrected QT (QTc) intervals. METHODS: Electrocardiograms (ECG) of all patients presenting to a regional toxicology service with moclobemide ingestion were reviewed. Cases where a cardiotoxic agent was coingested were excluded. QT and QTc parameters were compared with a comparison group of patients ingesting paracetamol or benzodiazepines. RESULTS: Of 75 patients where ECG were available, the median ingested dose was 4.5 g (interquartile range (IQR): 2.4-7.5; range: 0.6-18 g) and the median age was 34 years (IQR: 26-44). The mean QT interval was 415 ms (standard deviation (SD): 51 ms) with a mean QTc of 459 ms (SD: 44 ms), and were prolonged compared with the comparison group. Twelve female patients had a QTc > 500 ms and in seven of these causality was established based on a pre- or post-ECG with a QTc < 500 ms. Only 10% of the moclobemide cases had a heart rate (HR) > 100 beats per minute, making overcorrection of HR by Bazett's formula an unlikely cause of the findings. No cardiac arrythmias were observed other than one case of first-degree heart block. CONCLUSIONS: Moclobemide prolongs the QT and QTc intervals in overdose and a 12-lead ECG should be done on all moclobemide deliberate self-poisonings. Continuous cardiac monitoring for what is otherwise a relatively benign overdose would appear to be an inappropriate use of resources but can be considered in patients with a QTc > 500 ms or with known risks for QT prolongation.
Abstract: Anticholinergic Drug Scale (ADS) scores were previously associated with serum anticholinergic activity (SAA) in a pilot study. To replicate these results, the association between ADS scores and SAA was determined using simple linear regression in subjects from a study of delirium in 201 long-term care facility residents who were not included in the pilot study. Simple and multiple linear regression models were then used to determine whether the ADS could be modified to more effectively predict SAA in all 297 subjects. In the replication analysis, ADS scores were significantly associated with SAA (R2 = .0947, P < .0001). In the modification analysis, each model significantly predicted SAA, including ADS scores (R2 = .0741, P < .0001). The modifications examined did not appear useful in optimizing the ADS. This study replicated findings on the association of the ADS with SAA. Future work will determine whether the ADS is clinically useful for preventing anticholinergic adverse effects.
Abstract: BACKGROUND: Adverse effects of anticholinergic medications may contribute to events such as falls, delirium, and cognitive impairment in older patients. To further assess this risk, we developed the Anticholinergic Risk Scale (ARS), a ranked categorical list of commonly prescribed medications with anticholinergic potential. The objective of this study was to determine if the ARS score could be used to predict the risk of anticholinergic adverse effects in a geriatric evaluation and management (GEM) cohort and in a primary care cohort. METHODS: Medical records of 132 GEM patients were reviewed retrospectively for medications included on the ARS and their resultant possible anticholinergic adverse effects. Prospectively, we enrolled 117 patients, 65 years or older, in primary care clinics; performed medication reconciliation; and asked about anticholinergic adverse effects. The relationship between the ARS score and the risk of anticholinergic adverse effects was assessed using Poisson regression analysis. RESULTS: Higher ARS scores were associated with increased risk of anticholinergic adverse effects in the GEM cohort (crude relative risk [RR], 1.5; 95% confidence interval [CI], 1.3-1.8) and in the primary care cohort (crude RR, 1.9; 95% CI, 1.5-2.4). After adjustment for age and the number of medications, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM cohort (adjusted RR, 1.3; 95% CI, 1.1-1.6; c statistic, 0.74) and in the primary care cohort (adjusted RR, 1.9; 95% CI, 1.5-2.5; c statistic, 0.77). CONCLUSION: Higher ARS scores are associated with statistically significantly increased risk of anticholinergic adverse effects in older patients.
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.
Abstract: Our recent paper demonstrated the ability to predict in vivo clearance of flavin-containing monooxygenase (FMO) drug substrates using in vitro human hepatocyte and human liver microsomal intrinsic clearance with standard scaling approaches. In this paper, we apply a physiologically based pharmacokinetic (PBPK) modeling and simulation approach (M&S) to predict the clearance, area under the curve (AUC), andvalues together with the plasma profile of a range of drugs from the original study. The human physiologic parameters for FMO, such as enzyme abundance in liver, kidney, and gut, were derived from in vitro data and clinical pharmacogenetics studies. The drugs investigated include itopride, benzydamine, tozasertib, tamoxifen, moclobemide, imipramine, clozapine, ranitidine, and olanzapine. The fraction metabolized by FMO for these drugs ranged from 21% to 96%. The developed PBPK models were verified with data from multiple clinical studies. An attempt was made to estimate the scaling factor for recombinant FMO (rFMO) using a parameter estimation approach and automated sensitivity analysis within the PBPK platform. Simulated oral clearance using in vitro hepatocyte data and associated extrahepatic FMO data predicts the observed in vivo plasma concentration profile reasonably well and predicts the AUC for all of the FMO substrates within 2-fold of the observed clinical data; seven of the nine compounds fell within 2-fold when human liver microsomal data were used. rFMO overpredicted the AUC by approximately 2.5-fold for three of the nine compounds. Applying a calculated intersystem extrapolation scalar or tissue-specific scalar for the rFMO data resulted in better prediction of clinical data. The PBPK M&S results from this study demonstrate that human hepatocytes and human liver microsomes can be used along with our standard scaling approaches to predict human in vivo pharmacokinetic parameters for FMO substrates.