Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Maprotiline”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources
PubMed1991

Prophylactic efficacy of maprotiline on unipolar depression relapse.

BACKGROUND: Although antidepressant medications have been in use for about 30 years, the question remains about their utility in the prophylaxis of recurrent depression. The purpose of this study was to evaluate the efficacy of maprotiline, a tetracyclic antidepressant, for depression prophylaxis. METHOD: We conducted a vast, prospective, multicenter, double-blind, placebo-controlled study of 1141 outpatients suffering from depression and treated with maprotiline or placebo for 1 year. The very large size of the study population allowed for the testing of two drug doses. The study design included a pre-inclusion treatment phase that assured that all study patients had recently suffered from a depressive episode and were in remission at the time they were randomized into two treatment groups (1 and 1/2 tablet of maprotiline 75 mg) and two control groups (1/2 and 1 tablet of placebo). RESULTS: The actuarial relapse rate at 1 year was 16% for maprotiline 75 mg, 1 tablet; 23.8% for maprotiline 75 mg, 1/2 tablet; 31.5% for 1 tablet placebo, and 37.5% for 1/2 tablet placebo. The difference between each group is statistically significant, except for the difference between the two placebo groups. The actuarial incidence of adverse drug reactions during the year was not statistically significant between the treatment and control groups. CONCLUSIONS: This study demonstrates maprotiline's prophylactic effectiveness for depressive relapses, the 75-mg dose being more effective than the 37.5-mg dose. The patients' tolerance of maprotiline therapy was satisfactory at both doses with prolonged prescription.

Adolescent↗
PubMedDate not supplied

[Recurrence of unipolar depression and efficacy of maprotiline].

Although antidepressive treatments have been used for about thirty years, the question of their duration remains controverted. In fact, among the large number of therapeutic trials, only about fifteen control studies versus placebo, have evaluated the prophylactic advantage of a long-term antidepressive treatment. In order to complete the small number of products evaluated for this indication (imipramine, amitriptyline, zimelidine, nomifensine, fluoxetine), we have undertaken a vast multicenter study (130 psychiatrists), including 1,141 patients suffering from depression and treated with maprotiline, double-blind versus placebo, in ambulatory, for 1 year. The controlled trial was preceded with a pre-inclusion period in which 1,339 patients suffering from depression were treated, in an open study, with maprotiline at a dose of 75 to 150 mg. Only patients who were clinically improved during this preliminary study (MADRS less than 10), were included in the prophylactic evaluation phase, and divided into four groups: maprotiline 75 mg, maprotiline 1/2 tablet of 75 mg, placebo 1 tablet or placebo 1/2 tablet. The relapse was defined by a score exceeding 27 on the MADRS or exceeding 25 during two separate work-ups of 8 days or according to the experimenter's judgment. The actuarial relapse rate at 1 year was: 16% with 75 mg of maprotiline, 23.8% with 37.5 mg of maprotiline, 31.5% with one placebo tablet and 37.5% with 1/2 tablet of placebo, the difference being statistically significant between the 4 groups except for the "placebo" groups between them. In addition, the tolerance of maprotiline was satisfactory with prolonged prescription.

Adult↗
PubMed1986

Maprotiline: an antidepressant with an unusual pharmacological profile.

Maprotiline, which differs from other typical tricyclic antidepressants for its tetracyclic structure, is a highly selective inhibitor of norepinephrine reuptake. Despite its in vitro and in vivo inhibitory activity on NE uptake, 21 repeated daily injections of maprotiline (20 mg/kg i.p.) neither attenuated the norepinephrine-stimulated cAMP accumulation nor reduced the number of beta adrenergic recognition sites in rat frontal cortex. Also, the number of brain serotonin2 recognition sites labeled by [3H]ketanserin remained virtually unchanged in rats receiving 21 daily injections of maprotiline. [3H]Desmethylimipramine and [3H]mianserin specific binding sites were also unmodified by repeated maprotiline injections. However, after 3 weeks of daily administrations, maprotiline elicited a significant decrease in the number of [3H]flunitrazepam binding sites and a decrease in the apparent affinity of [3H]beta-carboline ethylester binding to crude synaptic membranes prepared from hippocampal and hypothalamic homogenates. These changes appear to be unrelated to modifications in the concentration of endogenous gamma-aminobutyric acid present in the membrane preparation, since the addition of 100 microM bicuculline to the incubation mixture decreases [3H]flunitrazepam binding to the same extent in saline- and maprotiline-treated rats. It is suggested that repeated maprotiline injections may elicit an increase in the hypothalamic and hippocampal tissue levels of an endogenous substance(s) which binds to the benzodiazepine/beta-carboline recognition sites.

Animals↗
PubMed1980

[The problem of hemoperfusion in poisonings: ineffectiveness in maprotiline poisoning].

A case of self-poisoning with maprotiline presenting with coma stage III was treated by resin hemoperfusion for 9 hours using an XAD-4 resin cartridge. Plasma levels of about 800 ng/ml maprotilin were initially found. After 5 hours of hemoperfusion progredient clinical improvement was noticed without decreasing tendency of the blood drug levels. The theoretical extraction efficiency calculated from the maprotiline blood levels and the perfusion rate yielded 50 mg for maprotiline and 16 mg for desmethylmaprotiline and was in good agreement with 60.5 mg of maprotiline and 17.3 mg of desmethylmaprotiline recovered from the resin cartridge at the end of the hemoperfusion. The in vitro binding capacity for maprotiline was estimated to be 230 mg per g of resin. These results demonstrate that XAD-4 resin efficiently binds maprotiline. However, because of the very low blood concentrations due to the large volume of distribution, whole body concentrations are minimally affected by resin hemoperfusion. Main complications consisted in thrombocytopenia extending over 24 hours after stopping hemoperfusion, anemia, a short initial decrease of blood pressure and an episode of premature ventricular beats.

Anthracenes↗
PubMed1990

Comparative effects of antidepressants, amitriptyline, and maprotiline on intraventricular conduction, effective refractory period, and incidence of ventricular arrhythmias induced by programmed stimulation in dog hearts after myocardial infarction.

The effects of amitriptyline and maprotiline, standard tricyclic and tetracyclic antidepressants, on intraventricular conduction, the effective refractory period (ERP), and the incidence of ventricular arrhythmias induced by programmed stimulation were studied and compared in dog hearts after myocardial infarction. Amitriptyline at doses of 1-3 mg/kg significantly slowed ventricular conduction of the infarcted zones in a frequency-dependent and dose-dependent manner. Amitriptyline at doses of 2 and 3 mg/kg slowed conduction slightly in normal zones. The ERP was prolonged by amitriptyline at a dose of 2 mg/kg. Amitriptyline increased the incidence of ventricular arrhythmias induced by programmed stimulation. Maprotiline at doses of 1-3 mg/kg slowed conduction in infarcted zones to a lesser extent as compared with amitriptyline, although severely depressed conduction in the infarcted zone was obviously slowed by maprotiline. Maprotiline did not increase the incidence of ventricular arrhythmias significantly. From the present results, maprotiline appears to have less cardiac toxicity than amitriptyline, although maprotiline produces a slight decrease in conduction of infarcted zones.

Action Potentials↗
PubMed1997

Dose escalation vs. continued doses of paroxetine and maprotiline: a prospective study in depressed out-patients with inadequate treatment response.

In view of the fact that controlled prospective studies on the benefits of dose escalation of the selective serotonin re-uptake inhibitor (SSRI) paroxetine are lacking, we conducted a double-blind, randomized, parallel-group multicentre study designed to compare the possible benefits of dose escalation of paroxetine and maprotiline in patients suffering from major or minor depression according to modified Research Diagnostic Criteria (RDC) with inadequate treatment response. The study sample consisted of 544 out-patients with different degrees of severity of depression. Patients received either 20 mg paroxetine (n = 271) or 100 mg maprotiline (n = 273) for the first 3 weeks in a double-blind manner. Response after 3 weeks was defined using explicit operationalized criteria. Patients with inadequate treatment response (paroxetine group, n = 86; maprotiline group, n = 88) were again randomized to either continuation of the previous dosage (paroxetine, n = 36; maprotiline, n = 48) or increased doses, i.e. 40 mg paroxetine (n = 50) or 150 mg maprotiline (n = 40), respectively. Intention-to-treat and completer analyses were performed. Defining response as a reduction in Hamilton Depression Rating Scale (17-item version) (HAMD-17) score of at least 50% from baseline, no significant benefits of dose escalation were found for either paroxetine or maprotiline. Stratification according to baseline severity of depression also revealed no significant benefits of dose escalation. After dose escalation, new adverse events that had not been present during treatment with lower doses rarely occurred. Our results support the view that a dose of 20 mg paroxetine is optimal for the acute treatment of depression in the majority of patients.

Adult↗
PubMed1988

A double-blind randomized study of clomipramine versus maprotiline in patients with idiopathic pain syndromes.

Seventy patients with idiopathic syndromes were treated with maprotiline, a noradrenaline reuptake inhibitor, or clomipramine, a serotonin reuptake inhibitor in a 6-week, double-blind, randomized, multicenter trial. Fifty-two patients completed the double-blind phase. Overall, 50% of the patients improved. Significant decreases were seen not only in the levels of pain but also in bodily discomfort, sadness an inner tension (determined by visual analogue scales, VAS). A decrease was also found in the frequency of sleep disturbances, intellectual and emotional inhibition, irritability, guilt feelings, retardation, sadness and suicidal ideas (observed ratings). Sixty-three percent of the subjects showed an overall improvement during treatment with clomipramine as compared to 36% during treatment with maprotiline (p less than 0.05). During clomipramine treatment significant decreases were seen on all the six VAS: sadness, bodily discomfort, inner tension, concentration difficulties, memory disturbances and pain. Bodily discomfort and pain were significantly reduced during maprotiline treatment. The effects produced by clomipramine were also significantly greater than the effects caused by maprotiline as concerns psychic anxiety and inhibition (VAS). The overall reduction in VAS was significantly greater with clomipramine when compared to maprotiline. The most important side effects were dry mouth (both drugs) and sweating (clomipramine). However, in the clomipramine group, 8 patients were excluded due to side effects as compared to 1 patient in the maprotiline group. Thus, the results indicate that antidepressants reduce not only pain but are also of clinical value in the treatment of patients with idiopathic pain syndromes. Drugs with pronounced effects on the serotonin reuptake are to be preferred.

Adult↗
PubMed1976

A double-blind comparison of lithium carbonate and maprotiline in the prophylaxis of the affective disorders.

A double-blind prospective study was carried out comparing the prophylactic effect of maprotiline and lithium carbonate over a period of one year in patients suffering from recurrent affective disorders. The average Affective Morbidity Index was lower, but not significantly so, in patients treated with lithium. A further analysis, based on dividing patients into those with no affective morbidity and those who showed some affective morbidity during the study, demonstrated lithium carbonate to be significantly superior to maprotiline both in the group as a whole and in unipolar depressives. A correlation between high plasma maprotiline concentration and low morbidity was observed and was in line with an earlier report. A highly significant negative correlation (r=-0-97; p less than 0-001) was found between plasma maprotiline concentration and body weight. Although the results showed lithium carbonate to be superior to maprotiline in the study, it should be emphasized that the plasma levels of lithium were constantly monitored and maintained at what is considered to be its optimum concentration, whereas the maprotiline treated patients were kept on a fixed dosage regime irrespective of plasma levels.

Adult↗
PubMed2006

Acute effects of maprotiline on learning, anxiety, activity and analgesia in male and female mice.

The acute effects of maprotiline (2.5, 5, 10, 15, 20 or 25 mg/kg) on learning, anxiety, activity and analgesia in male and female mice were evaluated. In addition to inhibitory avoidance learning, anxiety and locomotor activity were measured in the same animals using an elevated plus-maze. A study of the acute effects of maprotiline (15, 20 or 25 mg/kg) on analgesia was carried out in naive animals of both sexes. Maprotiline impaired inhibitory avoidance at doses of 15, 20 or 25 mg/kg. The highest dose produced an anxiolytic effect in females, and the doses of 20 and 25 mg/kg reduced locomotor activity. Analgesia was observed with the highest dose. The impairment of inhibitory avoidance by maprotiline would seem to be independent of the drug's influence on anxiety, is not shadowed by an instrumental performance deficit and, at least in the case of the highest dose, could be influenced by the drug's effects on analgesia. It is hypothesized that acquisition is the memory process principally affected by maprotiline, and in particular stimuli processing. The lack of sex differences in the effects of maprotiline on inhibitory avoidance supports the generalization of findings previously obtained only in males.

Analgesia↗
PubMed1988

Electrophysiological effects of maprotiline, a tetracyclic antidepressant agent, on isolated cardiac preparations.

We studied the effects of maprotiline, a tetracyclic antidepressant agent, on transmembrane potentials recorded from papillary muscles of guinea pigs and sinoatrial nodes of rabbits, using standard microelectrode techniques. Maprotiline (10-100 microM) produced dose-dependent decreases in the maximum rate of rise (Vmax) and action potential duration in papillary muscles, while the resting potential (Em) was not significantly affected. Maprotiline also shifted the Vmax-Em relation to more negative potentials. The slow action potentials of papillary muscles elicited by high [K+]o were also depressed by the drug application. In sinoatrial node cells, maprotiline (above 10 microM) reduced heart rate, Vmax, and action potential amplitude, and increased the action potential duration at half-amplitude. The slope of the phase 4 depolarization was decelerated by the drug. These results suggest that maprotiline depresses not only the fast inward sodium current but also the slow inward calcium current, and that relatively high concentrations of maprotiline exert an inhibitory effect on the electrical activity of the fast- and slow-response fibers of the hearts.

Action Potentials↗
PubMed1985

A double-blind trial comparing mianserin and maprotiline in depressed inpatients.

The antidepressant effects and side effects of mianserin and maprotiline were assessed in a double-blind trial in 62 inpatients (34 men and 28 women; mean age, 43.6 years) with primary depressive illness. For the first week of the trial, 32 patients received 30 mg/day of mianserin and 30 patients received 75 mg/day of maprotiline; for the next three weeks, the dosage of each drug was doubled. According to scores on the Hamilton Psychiatric Rating Scale for Depression, administered on days 0, 7, 14, 21, and 28, the antidepressant effects of the two drugs were virtually identical. Results of electrocardiographic and vectorcardiographic recordings and other measurements indicated that by day 28 the QRS duration was significantly longer (P less than 0.05) in the maprotiline group. On days 14 and 28, mean systolic blood pressure was significantly higher (P less than 0.05) in the maprotiline group. By day 28, the incidence of anticholinergic side effects--constipation and dry mouth--was significantly higher (P less than 0.05) in the maprotiline group. Although maprotiline's effects on heart functions never reached clinical significance, its anticholinergic side effects could be bothersome, especially to older patients.

Adolescent↗
PubMed1977

Efficacy, side-effects, plasma and blood levels of maprotiline (Ludiomil).

Two trials of maprotiline (Ludiomil) were performed in general practice. In the first study depressed patients were given either 75 mg of maprotiline in a single dose or 25 mg three times daily. Assessments of the severity of depression and of side-effects were made initially and following 1, 2 and 4 weeks' treatment. At each assessment measurements of plasma levels of maprotiline were made. A second trial was performed in which some patients receiving 75 mg single dose of maprotiline had whole blood levels of maprotiline assayed. Steady-state levels of maprotiline were achieved after one week but these levels showed considerable individual variability. No clear correlation emerged between clinical response, side-effects and plasma or blood levels. Some of the factors which may be responsible are discussed.

Adult↗
PubMedDate not supplied

[Maprotiline versus fluvoxamine: comparison of their effects on the hypothalamo-hypophyseal-thyroid axis].

The TRH test has been used in psychiatry these last 20 years. One of the most promising results is that concerning the possibility to use it to identify the best moment to stop a treatment after clinical recovery of the depressive episode. For that it is necessary to demonstrate an absence of intrinsic action of antidepressants on the HPT axis physiology. This overt, randomized study has compared the actions on T3, T4, basal TSH and its response to the TRH test after 75 mg/day of maprotiline and 100 mg/day of fluvoxamine, both administrated in depressed patients during 28 days. Forty patients (20 men and 20 women) were studied, 20 patients per treatment. The inclusion criteria were those of DSM III-R for major depression and dysthymia as well a minimum score of 25 at MADRS scale. Blood samples for T3, T4 and basal TSH dosages were made before TRH intranasal administration (2 mg) at days 1 and 28 of the treatment. We haven't observed any difference before treatment between the 2 groups for clinical and biological studied parameters. After treatment both antidepressants produced equivalent improvement of depression evaluated by MADRS (fluvoxamine:dMADRS = 16.95 +/- 7.11; maprotiline: dMADRS = 17.10 +/- 6.84. t = 0.07, NS). T3 and T4 variations between the beginning and the end of the study weren't also significantly different between the 2 groups. Basal TSH was increased in the maprotiline group but decreased in the fluvoxamine group resulting in a significant difference (fluvoxamine: dTSH = 0.31 +/- 0.76 mUI/l. Maprotiline : dTSH = -0.23 +/- 0.66 mUI/l. t = 2.40, p < 0.02). The TSH response to TRH was decreased in the fluvoxamine group (ddTSH = 0.24 +/- 6.65 mUI/l. dAUC = 103.98 +/- 596.84 mUI/l) while it was increased in the maprotiline group (ddTSH = -3.59 +/- 5.88 mUI/l. dAUC = -355.80 +/- 505.67 mUI.min/l). The difference between the 2 treatments was not significant when evaluated by ddTSH (t = 1.53, NS) but it became significant if evaluated by dAUC (t = 2.63, p < 0.01). As we could demonstrate an absence of influence of the clinical evolution between both groups in the hormonal variations observed, we concluded to a intrinsic difference action on HPT axis between fluvoxamine and maprotiline. This difference could be linked to the different aminergic action of these 2 antidepressants.

Adult↗
PubMed1983

Maprotiline in the treatment of endogenous depression: comparison of therapeutic effect with serotonin level in blood platelets.

In blood platelets of untreated patients with endogenous depression a significantly lower concentration of serotonin (5-HT) was found than in healthy persons (P less than 0.05). The patients were afterwards divided into two groups: group I with mild symptoms of depression (total scores by Hamilton Depression Rating Scale below 40) and group II with severe depression (total scores above 40). The gradual diminishing of symptoms in both groups was accompanied by no change in 5-HT level in the first group and by progressive and well marked increases in platelet 5-HT content in the second one, attaining average normal values at the end of week 3 of treatment with maprotiline. In in vitro experiments maprotiline inhibited the uptake of 5-HT into blood platelets of healthy persons less than doxepin. After injection of maprotiline in rats (50 mg/kg IP) the turnover rate of 5-HT in the brain was only marginally affected if measured by 5-HT rise and 5-hydroxyindoleacetic acid (5-HIAA) decline after administration of the MAO inhibitor pargyline, or by estimation of 5-HIAA increase after blocking active transport with probenecid. However, after treatment with maprotiline alone, the 5-HIAA level in the rat brain was significantly increased, although the concentration of 5-HT was not altered. These results suggest: a) the possibility of an action of maprotiline on serotoninergic neurons and b) the suitability of blood platelets as a model for such an investigation.

Adult↗
PubMed1995

Cardiovascular effects of fluvoxamine and maprotiline in depressed patients.

In the choice of an antidepressant drug the clinician must often consider the presence of a cardiovascular comorbidity in depressed patients. In the present study the cardiovascular effects of fluvoxamine and maprotiline were compared in a double-blind trial in which the quantitative changes in ECGs were assessed before and during a 3-week treatment. A total of 33 patients (mean age 44 years; range 20-65 years) with major depressive disorder (RDC) who were free from clinically relevant organic diseases were investigated. After a 7-day wash-out period, a 3 week treatment phase was started with 200 mg daily of either fluvoxamine (n = 18) or maprotiline (n = 15). On days 0, 7, 14 and 21 a 12-lead standard ECG was performed and the drug plasma levels were determined. All ECGs were analysed in a blind fashion by an internist. Maprotiline caused a significant prolongation of the PR interval (P < 0.001) and of the QRS interval (P < 0.01) was well as an increase in heart rate (P < 0.001). The QTc interval was only tendentially prolonged (P < 0.10) and the P-wave duration and T-wave amplitude were not affected by maprotiline. No significant changes in ECG parameters were observed during treatment with fluvoxamine; and there was a nonsignificant trend (P < 0.10) for a lower heart rate during treatment. Blood pressure was not affected by treatment with either antidepressant. In both groups no significant correlations were found between ECG findings and the plasma levels of the drugs. Our results confirm that fluvoxamine in therapeutic dose causes no alteration in surface ECG regarding cardiac conduction and repolarization. Conversely, maprotiline caused a significant prolongation of atrioventricular and intraventricular conduction and a rise in heart rate. Although these effects were not clinically relevant in our sample of patients without overt heart disease, they should be taken into account when treating depressed patients with concomitant cardiac disease.

Adult↗
PubMed1993

Plasma concentrations of fluvoxamine and maprotiline in major depression: implications on therapeutic efficacy and side effects.

We examined the relationship between plasma concentrations of specific acting antidepressants (fluvoxamine/maprotiline) and clinical improvement as well as the impact of the magnitude of the plasma concentration of these antidepressants on side effects. Patients (32 patients with major depression) were treated within a double-blind parallel trial for four weeks and plasma concentrations were obtained before, on days 8 and 28 of the trial. Although there was a fixed-flexible dosage design it was apparent that 16 patients (89%) of the fluvoxamine group and all patients of the maprotiline group received a dosage between 200 and 300 mg/day in the last week of the trial. Plasma concentrations (mean +/- SD micrograms/l) of fluvoxamine were 125 +/- 91 and 142 +/- 108 on days 8 and 28, respectively and the range of fluvoxamine plasma concentrations on day 28 was from 20 to 417 micrograms/l. Plasma concentrations (mean +/- SD micrograms/l) of maprotiline were 146 +/- 62 and 202 +/- 134 on days 8 and 28, respectively and the range of maprotiline plasma concentration on day 28 was from 12 to 428 micrograms/l. There was no linear relationship between plasma concentrations of both antidepressants (fluvoxamine/maprotiline) and oral dosage. Whereas there was no correlation between fluvoxamine concentration and clinical response there was a tendency that higher maprotiline concentrations were associated with a better antidepressive efficacy at the end of the trial. Higher concentrations of fluvoxamine as well as of maprotiline were significantly (P < 0.05) associated with more side effects.

Adult↗
PubMed2001

Gender differences in the efficacy of fluoxetine and maprotiline in depressed patients: a double-blind trial of antidepressants with serotonergic or norepinephrinergic reuptake inhibition profile.

BACKGROUND: Depression has emerged as a contrastive area of gender differences in psychiatry, as epidemiological data has consistently shown depression is twice as common in women as men. The pharmacodynamic effect of antidepressants may also show gender differences, as suggested by reports of better response of young women to non-tricyclic antidepressants. METHODS: The antidepressive effect of an SSRI (fluoxetine) and a tetracyclic antidepressant with selective norepinephrine reuptake inhibitory effect (maprotiline) was compared in a 6-week, double-blind trial of 105 depressed patients. RESULTS: No significant difference was observed in the change of HAMD17 total score from baseline to week 6 between fluoxetine- and maprotiline-treated patients. A significant difference was observed in females (fluoxetine, -17.8; maprotiline, -13.9; P=0.017) between treatment groups, but not in males. Amongst females, the difference was significant in women aged <44 years (fluoxetine, -18.4; maprotiline, -12.9; P=0.023) but not > or =44 years. CONCLUSIONS: Females in their reproductive period are more responsive to SSRI (fluoxetine) than norepinephrinergic tetracyclic antidepressant (maprotiline) treatment. Normal cyclical ovulation, and estrogen release may have a clinically relevant pharmacodynamic interaction with serotonergic antidepressants.

Adrenergic Uptake Inhibitors↗
PubMed2002

Cytochrome P450 enzymes contributing to demethylation of maprotiline in man.

From case reports of patients treated with the tetracyclic antidepressant drug maprotiline, it appears that this drug is subject to polymorphic metabolism. Thus, we studied formation of the major maprotiline metabolite desmethylmaprotiline to identify the human cytochrome P-450 enzymes (CYP) involved. In incubations with human liver microsomes from two different donors, the substrate maprotiline was used at five different concentrations (5 to 500 microM). For selective inhibition of CYPs, quinidine (0.5-50 microM; CYP2D6), furafylline (0.3-30 microM; CYP1A2), ketoconazole (0.2-20 microM; CYP3A4), mephenytoin (20-200 microM; CYP2C19), chlorzoxazone (1-100 microM; CYP2E1), sulphaphenazole (0.2-100 microM; CYP2C9) and coumarin (0.2-100 microM; CYP2A6) were used. Desmethylmaprotiline concentrations were measured by HPLC, and enzyme kinetic parameters were estimated using extended Michaelis-Menten equations with non-linear regression. Relevant inhibition of the desmethylmaprotiline formation rate was observed in incubations with quinidine, furafylline and ketoconazole only. Formation rates of desmethylmaprotiline were consistent with a two enzyme model with a high (K(M)=71 and 84 microM) and a low (K(M)=531 and 426 microM) affinity site for maprotiline in the two samples, respectively. The high affinity site was competitively inhibited by quinidine (K(i,nc) 0.13 and 0.61 microM), the low-affinity site was non-competitively inhibited by furafylline (K(i,nc) 0.11 and 1.3 microM). Thus it appears that CYP2D6 and CYPIA2 contribute to maprotiline demethylation. Based on the parameters obtained, for plasma concentrations of 1 microM 83% (mean) of desmethylmaprotiline formation in vivo is expected to be mediated by CYP2D6 while 17% only may be attributed to CYPIA2 activity.

Cells, Cultured↗