desmethylclomipramine and 8-hydroxyclomipramine

After an initial placebo week, 37 depressed inpatients were treated with the fixed dose of 75 mg clomipramine b.d. A sparteine test was carried out during the placebo period and again during the second week of active therapy. Blood for drug assay was collected at the end of the inter-dose interval in the (morning) at weekly intervals. Clomipramine and four metabolites (desmethylclomipramine, didesmethylclomipramine, 8-hydroxyclomipramine, and 8-hydroxydesmethylclomipramine) in plasma were assayed by reversed phase HPLC. The clomipramine and desmethylclomipramine steady-state plasma levels varied by factors of 11 and 9, respectively, and the clomipramine/8-hydroxyclomipramine and desmethylclomipramine/8-hydroxydesmethylclomipramine ratios both varied by 7-fold. During the placebo week, 36 patients were phenotyped as extensive metabolizers (EM) (metabolic ratio, MR, 0.1-2.0), and one patient was phenotyped as a poor metabolizer (PM) (MR > 300). During clomipramine treatment, one patient changed phenotype from EM to PM (MR = 140). In the EM, the median of the MR increased from 0.4 to 2.3. There was a statistically significant correlation between the MR before and during clomipramine treatment, even when the PM was excluded. Neither the steady-state plasma clomipramine levels nor the clomipramine/desmethylclomipramine ratios showed a significant correlation with the MR. In contrast, the desmethylclomipramine and didesmethylclomipramine steady-state levels and the desmethylclomipramine/8-hydroxydesmethylclomipramine and clomipramine/8-hydroxyclomipramine ratios showed a significant positive correlation with the MR. The PM had the highest steady-state plasma desmethylclomipramine level and the highest desmethylclomipramine/8-hydroxydesmethylclomipramine ratio. These correlation coefficients (rs) were generally increased when the correlation analyses were based on the MR obtained during clomipramine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Clomipramine; Cytochrome P-450 Enzyme System; Debrisoquin; Depression; Female; Humans; Male; Middle Aged; Oxidation-Reduction; Phenotype; Polymorphism, Genetic; Sparteine

Because metabolites play a major role in the clinical response to clomipramine, the objective of the current study was to develop a population model and evaluate its performance to describe the pharmacokinetic profiles of clomipramine (C) and its active metabolites desmethylclomipramine (DC), 8-hydroxy-clomipramine (OHC) and 8-hydroxy-desmethylclomipramine (OHDC). A first sample of 14 patients served for development of a 2-molecule C and DC model, which was shown to provide reasonable estimates of AUC-based clearances, as well as precise estimation of interindividual variability. Simulated data, generated to mimic a semi-rich sampling design and chronic treatment with clomipramine, indicated that clearance estimation was feasible under routine treatment conditions. A second sample of 30 patients, recruited prospectively and followed for a median 4-week period, was used to extend the 2-molecule model to a 4-molecule model. Goodness-of-fit assessment revealed that model-predicted concentrations were reasonably close to observed concentrations for a majority of patients. Interindividual variability was 50% to 60% for hydroxylation and desmethylation clearances, and residual variability was 30%. The proposed model incorporates much of what is known about the metabolism of clomipramine and may valuably integrate the influence of genetic and environmental factors on each metabolic pathway.

Topics: Adult; Aged; Antidepressive Agents, Tricyclic; Clomipramine; Computer Simulation; Depression; Drug Administration Schedule; Female; Humans; Hydroxylation; Male; Middle Aged; Models, Biological; Prospective Studies; Reproducibility of Results

Women with postpartum-onset obsessive compulsive disorder may elect treatment with clomipramine. There is minimal information to guide the clinician who must advise breastfeeding women about clomipramine therapy.. Four clomipramine-treated breastfeeding mother-infant pairs were assessed for serum concentrations of clomipramine, N-desmethylclomipramine, and corresponding 8-hydroxymetabolites.. Although the mothers exhibited a wide range of serum concentrations, the parent drug and metabolites were either nondetectable or below the quantifiable limit in the sera of all infants. No adverse clinical effects were observed.. This report adds to the growing literature that suggests that tricyclic use during breastfeeding rarely results in measurable drug levels in infant sera.

Topics: Adult; Breast Feeding; Clomipramine; Female; Half-Life; Humans; Infant; Infant, Newborn; Male; Obsessive-Compulsive Disorder; Pregnancy; Pregnancy Complications

We measured the plasma concentrations of clomipramine and its metabolites, N-desmethylclompiramine, 8-hydroxy-N-desmethylclomipramine, 8-hydroxyclomipramine in 65 depressed patients with subtypes of DSM-III-R mood disorders receiving clomipramine hydrochloride. There were large interindividual variations in the concentrations of the parent and each of the metabolic compounds, though the overall correlations between drug concentrations and daily doses of clomipramine were highly significant. Metabolic ratios for both desmethylation and hydroxylation varied by 15-35-fold interindividually. Discriminant analysis of the data from drug concentrations and scores of Global Assessment of Functioning revealed that it is useful to monitor the concentrations of both desmethylated and hydroxylated metabolites in order to predict the clinical effects of clomipramine.

Topics: Adolescent; Adult; Aged; Biotransformation; Bipolar Disorder; Clomipramine; Depressive Disorder; Drug Monitoring; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Psychiatric Status Rating Scales; Structure-Activity Relationship; Treatment Outcome

We measured the concentrations of clomipramine and its metabolites, N-desmethylclomipramine, 8-hydroxy-N-desmethylclomipramine, and 8-hydroxyclomipramine in plasma in 92 Japanese psychiatric patients receiving clomipramine hydrochloride (Anafranil, Ciba-Geigy Japan Limited, Takarazuka, Japan) by high-performance liquid chromatography. Although there were large interindividual variations of total drug concentrations and concentrations of parent or intermediate metabolic compounds in plasma, significant positive correlations were observed between these drug concentrations and daily doses of clomipramine hydrochloride (milligrams per kilogram of body weight). The metabolic ratios for both desmethylation and hydroxylation varied substantially with 30- to 90-fold interindividual variations. Frequency distribution histograms and probit analyses of these parameters identified only one possible poor hydroxylator but no poor desmethylator of clomipramine. These results suggest that there are large interindividual variations of capacities for hydroxylation and desmethylation of clomipramine in the Oriental population and that therapeutic drug monitoring is essential in clinical practice to reduce the adverse effects of clomipramine and to prevent poor response to clomipramine.

Topics: Adolescent; Adult; Aged; Biotransformation; Clomipramine; Dose-Response Relationship, Drug; Ethnicity; Female; Humans; Japan; Male; Mental Disorders; Middle Aged

A procedure for the determination of clomipramine and its 8-hydroxy, demethyl, 8-hydroxydemethyl and didemethyl metabolites in plasma and urine by high-performance liquid chromatography with electrochemical detection is described. A 1-ml plasma or urine sample is made alkaline with a carbonate buffer (pH 9.8) and extracted with 20% ethyl acetate in n-heptane. After back-extraction into an acid phosphate buffer (pH 2.4), an aliquot is injected into a 5-microns ion-paired reversed-phase column and eluted with a mobile phase containing a phosphate buffer with tetramethylammonium chloride-acetonitrile (57:43). The detection is coulometric with a first cell at +0.40 V, a second at +0.73 V and a guard cell set at 0.75 V for oxidation of the mobile phase. The method provides recoveries in the general range of 80-110% and a day-to-day precision of 3.7-8.8%, depending on the compound. The minimum quantifiable level for all compounds was 0.2 ng/ml with a 20-microliters injection. Steady-state plasma concentration data and urinary levels are reported for 24 depressed patients receiving daily either 75-150 mg orally or 50-75 mg by infusion.

Topics: Chromatography, High Pressure Liquid; Clomipramine; Drug Stability; Electrochemistry; Humans