In five individuals serial moclobemide concentrations were measured. peak plasma concentration was delayed in two patients where prepeak samples were obtained. time data using a first-order elimination, one-compartment disposition model. Data points prior to peak plasma concentration were ignored and an exponential decay was fitted to the plasma concentrationCtime data and half-life was calculated. Half-lives for two of the three metabolites were also decided. Analysis and curve fitting were performed using GraphPad Prism version 3.02 for Windows (GraphPad Software, San Diego, CA, USA). Statistical analysis For descriptive statistics, means and standard deviations (SD) are quoted for normally distributed data, while medians and interquartile ranges (IQR) are used for nonparametric data. For comparison of two groups, unpaired = 0.028 **= 0.034 *** 0.01 ****= 0.020. NS, Not significant 1all four had coingested a tricyclic antidepressant 2all had coingested proconvulsant drugs: dothiepin, doxepin, venlafaxine (3) and thioridazine 3asystole occurred in one patient who coingested metoprolol and ventricular tachycardia occurred in another who coingested dothiepin. All major Clavulanic acid complications in the 106 patients, including seizures and coma, occurred in patients taking coingestants and could be accounted for by the coingested drug (Table 2). The median dose Clavulanic acid of moclobemide in the 73 patients coingesting other drugs was 4 g (IQR 2.3C6.7), which was significantly less than the moclobemide-alone overdoses (= 0.028). Table 2 Comparison of serotonergic effects and complications between moclobemide alone overdoses and moclobemide overdoses where a serotonergic coingestant was taken. 0.01 ** 0.0001. The 33 cases of moclobemide-alone overdoses are compared with the 21 cases where a serotonergic agent was taken as a coingestant in Table 2. Eleven (52%) of the 21 patients coingesting a serotonergic drug developed serotonin toxicity, which was significantly more than for moclobemide alone overdoses, one of 33 (3%), [odds ratio (OR) 35, 95% confidence interval (CI) 4, 307; 0.0001]. In six of the 11 cases the features were consistent with severe serotonin toxicity necessitating sedation and intubation of Clavulanic acid the patient. There was a significantly increased LOS for serotonergic coingestant overdoses of 39 h (IQR 20C79 h) moclobemide alone overdoses 12 h (IQR 9C20 h) and a significantly increased rate of ICU admission of 11 in 22 Clavulanic acid (52%) one in 33 (3%) (OR 35, 95% CI 4, 307; 0.0001). The coingested agent in these 11 patients was an SSRI in five patients, venlafaxine in four patients, doxepin and tranylcypromine in one patient each. No patient ingested more than 30 defined daily doses (DDD) of the coingestant, one patient coingested only 150 mg of venlafaxine and another 750 mg of venlafaxine. The patient coingesting 150 mg venlafaxine developed severe serotonin toxicity requiring intubation and paralysis (patient B). Toxicokinetics In five patients who developed significant serotonin toxicity serial plasma concentrations of moclobemide and three metabolites were measured and plotted as plasma concentrationCtime curves. Physique 2 shows the plasma concentrationCtime curves for the five patients. Information on coingestants taken in these five cases was based on the history, and was confirmed in each case by HPLC (Table 3). Open in a separate window Physique 2 Plasma concentrationCtime profile for moclobemide Mouse monoclonal to LAMB1 (?) (Ro 11-1163) and three of its metabolites, the N-oxide metabolite (Ro 12-5637 ()), the oxo-metabolite (Ro 12-8095 ()) and the ring-opened Clavulanic acid metabolite (Ro 16-3177 (?)) for five of the patients. Table 3 Toxicokinetic information on five patients where serial plasma concentrations were measured. time is shown in Physique 3. Included in the physique are data from pharmacokinetic studies and a linear regression of these data , as well as two other overdose cases where data were available . estimated dose plot (top) and plasma elimination half-life dose (bottom). PK data are taken from Mayersohn time shows that there.