Trazodone Concentration Research Articles

Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective.

Many psychiatric patients smoke, and are believed to be heavier smokers than those without psychiatric disorders. Cigarette smoking is one of the environmental factors that contributes to interindividual variations in response to an administered drug. Polycyclic aromatic hydrocarbons (PAHs) present in cigarette smoke induce hepatic aryl hydrocarbon hydroxylases, thereby increasing metabolic clearance of drugs that are substrates for these enzymes. PAHs have been shown to induce 3 hepatic cytochrome P450 (CYP) isozymes, primarily CYP1A1, 1A2 and 2E1. Drug therapy can also be affected pharmacodynamically by nicotine. The most common effect of smoking on drug disposition in humans is an increase in biotransformation rate, consistent with induction of drug-metabolising enzymes. Induction of hepatic enzymes has been shown to increase the metabolism and to decrease the plasma concentrations of imipramine, clomipramine, fluvoxamine and trazodone. The effect of smoking on the plasma concentrations of amitriptyline and nortriptyline is variable. Amfebutamone (bupropion) does not appear to be affected by cigarette smoking. Smoking is associated with increased clearance of tiotixene, fluphenazine, haloperidol and olanzapine. Plasma concentrations of chlorpromazine and clozapine are reduced by cigarette smoking. Clinically, reduced drowsiness in smokers receiving chlorpromazine, and benzodiazepines, compared with nonsmokers has been reported. Increased clearance of the benzodiazepines alprazolam, lorazepam, oxazepam, diazepam and demethyl-diazepam is found in cigarette smokers, whereas chlordiazepoxide does not appear to be affected by smoking. Carbamazepine appears to be minimally affected by cigarette smoke, perhaps because hepatic enzymes are already stimulated by its own autoinductive properties. Cigarette smoking can affect the pharmacokinetic and pharmacodynamic properties of many psychotropic drugs. Clinicians should consider smoking as an important factor in the disposition of these drugs.

Pharmacokinetics of trazodone and its major metabolite m-chlorophenylpiperazine in plasma and brain of rats.

Sprague-Dawley rats were used as models for single trazodone administration (males), continuous adminstration and dose proportionality experiments (males, females, pregnant females). Plasma and brain tissue were analysed for trazodone and its active metabolite, m-chlorophenylpiperazine (m-CPP). Fetal exposure to trazodone and m-CPP was assessed and differences in their steady-state plasma concentration were sought between adult males and females. Both trazodone and m-CPP rapidly appeared in plasma and brain tissue following a single intraperitoneal trazodone dose with brain concentrations exceeding those in plasma. Plasma concentrations of m-CPP were lower than those of trazodone but exceeded them in brain tissue. Chronic administration using osmotic mini-pumps revealed a significant linear relationship between trazodone concentration in plasma and brain at steady-state (r=0.96, p<0.0001). No simple relationship was found between plasma and brain tissue concentration for m-CPP. In contrast to observations following single trazodone administration, m-CPP concentrations at steady-state were lower than trazodone concentrations in brain tissue, suggesting a lack of stationarity in the disposition of trazodone over time. No significant differences in plasma or brain tissue drug concentrations relative to administered trazodone dose were observed between male and female rats, nor between pregnant and non-pregnant females. Trazodone and m-CPP were both detected in fetal and placental tissues, with placenta having the highest concentrations. The data suggest that neuropharmacological studies of trazodone could yield different results depending upon the route and schedule of drug administration. Maternally administered trazodone, like many other antidepressants, is distributed to fetal tissues in rodents, reaffirming the need for caution in treating pregnant women with psychoactive drugs.

Ion-selective electrode for the determination of trazodone in tablets.

A coated wire trazodone-selective electrode based on incorporation of trazodone-tetraphenylborate ion pair in a poly(vinylchloride) coating membrane was constructed. The influences of membrane composition, temperature, pH of the test solution, and foreign ions on the electrode performance were investigated. The electrode showed a Nernstian response over a trazodone concentration range from 1.41 x 10(-5) to 0.89 x 10(-2) M, at 25 degrees C, and was found to be very selective, precise, and usable within the pH range 2.4-9.0. The standard electrode potentials, E degree, were determined at 20, 25, 30, 35, 40 and 45 degrees C and used to calculate the isothermal temperature coefficient (dE degree/dT) of the electrode. Temperatures higher than 45 degrees C seriously affected the electrode performance. The electrode was successfully used for potentiometric determination of trazodone hydrochloride both in pure solutions and in pharmaceutical preparations.

Correlation between steady-state plasma concentrations of mianserin and trazodone in depressed patients.

The correlations between steady-state plasma concentrations of mianserin and its active metabolite desmethylmianserin and those of trazodone and its active metabolite m-chlorophenylpiperazine (m-CPP) were examined in 19 depressed patients. Ten patients received first mianserin (30 mg per day) and second trazodone (150 mg per day), while 9 patients received these treatments in the opposite sequence, with at least 2-week intervals between the two phases. Blood was sampled at steady state, 1-3 weeks after initiation of each treatment. Plasma concentrations of mianserin, the separate enantiomers S(+)- and R(-)-mianserin, desmethylmianserin, trazodone and m-CPP were measured by means of high-performance liquid chromatography. There was a significant correlation between steady-state plasma concentrations of trazodone and total mianserin (r = 0.59) or S(+)-mianserin (r = 0.57), but not R(-)-mianserin (r = 0.33). The present study thus suggests that the metabolic capacity of mianserin, especially the more active S(+)-enantiomer, and that of trazodone correlate to each other. This finding supports the previous suggestions that cytochrome P4502D6 is involved in the metabolism of mianserin and trazodone.

Determination of trazodone and its metabolite, 1-m-Chlorophenyl-piperazine, in human plasma and red blood cell samples by HPLC

Objectives: To develop an HPLC method for the analysis of trazodone and its metabolite, 1-m-chlorophenyl-piperazine (m-CPP), in human plasma and red blood cells. Design and Methods: The analytes were extracted by heptane containing 1.5% isoamyl alcohol, back extracted into phosphoric acid and analyzed by reverse phase HPLC with UV detection. Results: In seven randomly selected, male, human subjects plasma concentrations (nmol/I) were 380–5841 for trazodone and 14–237 for m-CPP while those in packed red blood cells were 98–634 for trazodone and 15–155 for m-CPP. Plasma trazodone concentrations were 4–11-fold higher than those in red blood cells while those of m-CPP were about equal. This may be the first report on concentrations of trazodone and m-CPP in human red blood cells. This sensitive method can be used for monitoring trazodone and m-CPP in human plasma and red blood cells.

Increases in Plasma Concentration of m-Chlorophenylpiperazine, but not Trazodone, with Low-Dose Haloperidol

Our previous study suggested that cytochrome P4502D6 (CYP2D6) is involved in the metabolism of trazodone and its active metabolite, m-chlorophenylpiperazine (m-CPP). The purpose of this study was to examine the degrees of increase in plasma concentrations of trazodone and m-CPP induced by haloperidol, which is an inhibitor of CYP2D6. The subjects were nine depressed inpatients receiving trazodone at bedtime (150 mg in seven patients and 300 mg in two) for 2-19 weeks. Haloperidol at 4 mg/day was coadministered for 1 week, and blood samplings were taken before and after the coadministration. Contrary to our expectation, haloperidol did not significantly increase the mean plasma trazodone concentration (810 +/- 382 vs. 856 +/- 357 ng/ml). However, haloperidol significantly increased (p < 0.01) the mean plasma m-CPP concentration (78 +/- 31 vs. 92 +/- 34 ng/ml).

Plasma concentrations of trazodonb and m-chlorophenylpiperazine at steady state can be predicted from those after an initial dose of trazodone

1. 1.The authors studied the correlations between plasma concentrations of trazodone and mCPP at steady state and those after an initial dose of trazodone. 2. 2.Fifteen depressed patients received trazodone 150 mg at bedtime for 3 weeks, and blood samplings were taken 12 h after the initial dose and 12 h after the last dose at each week. Plasma concentrations of trazodone and mCPP were measured by high-performance liquid chromatography. 3. 3.Plasma concentration of mCPP, but not trazodone, was significantly higher at each week than after initial dosing. 4. 4.For both trazodone and mCPP, significant linear relationships were found between plasma concentration after initial dosing and the average of 3 weeks' plasma concentrations. 5. 5.The present study thus suggests that plasma concentrations of trazodone and mCPP at steady state can be predicted from those after an initial dose of trazodone .

Effects of carbamazepine coadministration on plasma concentrations of trazodone and its active metabolite, m-chlorophenylpiperazine.

Effects of carbamazepine coadministration on plasma concentrations of trazodone and its active metabolite, m-chlorophenylpiperazine (m-CPP) were studied in six depressed patients treated with trazodone. The daily dose of trazodone was 150 mg in three cases and 300 mg in three cases. Carbamazepine, 400 mg/day, was coadministered for 4 weeks, and blood samples were taken before carbamazepine addition and at weekly intervals after the addition. Carbamazepine significantly (p < 0.01) decreased plasma concentrations of not only trazodone but also m-CPP at each week. On the average, plasma concentrations of trazodone and m-CPP at 4 weeks were 24 and 40% of the corresponding precarbamazepine values. This study thus suggests that carbamazepine coadministration decreases plasma concentrations of trazodone and m-CPP by inducing the metabolism of these compounds.

Effects of various factors on steady state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine.

Effects of various factors on steady state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine (mCPP) were studied in 43 depressed patients (19 males, 24 females) receiving trazodone 150 mg at bedtime for 1-3 weeks. Sixteen cases were smokers, and 19 cases were also receiving various benzodiazepines. The means (and ranges) of plasma concentrations of trazodone and mCPP, and the mCPP/trazodone ratio were 619 (251-1059) ng/ml, 59 (32-139) ng/ml and 0.100 (0.044-0.219), respectively. Smokers had significantly (p < 0.05) lower plasma concentrations of trazodone and higher mCPP/trazodone ratios than non-smokers. Age, sex and co-administration of benzodiazepines did not affect any plasma concentrations or the mCPP/trazodone ratio. In 11 cases where the dose was increased to 300 mg, neither plasma concentration/dose ratios nor the mCPP/trazodone ratio changed significantly. The present study thus suggests that: (1) there is a large Interindividual variation in the metabolism of trazodone; (2) smoking enhances the metabolism, but age, sex and co-administration of benzodiazepines do not affect it; (3) trazodone and mCPP have linear kinetics.

Inhibition of trazodone metabolism by thioridazine in humans.

To clarify the involvement of cytochrome P4502D6 (CYP2D6) in the metabolism of trazodone, the effects of coadministration of thioridazine, which is an inhibitor of this isozyme, on plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine (m-CPP) were studied. The subjects were 11 depressed patients receiving trazodone at bedtime for 1-18 weeks. The dose was 150 mg in 10 patients and 300 mg in one. Thioridazine 40 mg/day was coadministered for 1 week, and blood samplings were performed before and after the coadministration. Thioridazine significantly (p < 0.001) increased plasma concentrations of both trazodone (713 +/- 252 vs. 969 +/- 370 ng/ml) and m-CPP (61 +/- 22 vs. 94 +/- 34 ng/ml). The present study thus suggests that CYP2D6 is involved in the metabolism of trazodone.

On-line automated sample preparation-capillary gas chromatography for the analysis of plasma samples

An automated sample preparation module, (the automated sample preparation with extraction columns, ASPEC), was interfaced with a capillary gas chromatograph (GC) by means of an on-column interface. The system was optimised for the determination of the antidepressant trazodone in plasma. The clean-up of untreated plasma was carried out with disposable C18 cartridges, using several washing steps. The analyte was desorbed with methanol, the extract was diluted on-line with buffer and preconcentrated on a PLRP-S trapping column. The trapping column was dried by purging with nitrogen gas. Desorption (phase switching) of the trapping column was carried out with ethyl acetate which was introduced into a retention gap using partially concurrent solvent evaporation conditions. Trazodone was determined by GC with flame ionisation detection (FID). With a 1 ml sample, this resulted in a detection limit for trazodone in plasma of 3 ng/ml. The system showed good linearity and repeatability in the range 0.01–1 μg/ml, thus covering the range of pharmacokinetic/dynamic-to-therapeutic concentrations of trazodone in plasma.

Single dose pharmacokinetics of trazodone in healthy subjects.

Eight healthy subjects were administered trazodone-HCl orally (100 mg) with and without food and by infusion in a three way cross-over study. Unchanged trazodone was determined in serum and urine by high performance liquid chromatography after an alkaline extraction. Absorption of trazodone was irregular in fasting subjects and improved after food intake. Food intake significantly decreased the maximum serum concentrations of trazodone from 1.88 +/- 0.42 to 1.47 +/- 0.16 micrograms/ml, and increased the time for reaching maximum concentration from 1.3 +/- 0.8 hr to 2.0 +/- 1.5 hr. No differences were observed in the total amount of trazodone absorbed with or without food with bioavailability values of 65 +/- 6 and 63 +/- 4 per cent, respectively. The apparent volume of distribution and total body clearance for trazodone were estimated to 0.84 +/- 0.16 l/kg and 5.3 +/- 0.9 l/hr, respectively. The terminal elimination half-life of 7.3 +/- 0.8 hr showed no significant differences between the different ways of administration. Urinary excretion of unchanged trazodone during 26 hr was less than 0.13 per cent of the administered dose, suggesting a high degree of trazodone metabolism. Earlier statements of enterohepatic circulation of trazodone and pharmacokinetic differences between males and females were not confirmed by the present study. Due to the irregular absorption in fasting subjects, trazodone should preferably be administered after food.

Evidence for a Linear Relationship Between Plasma Trazodone Levels and Clinical Response in Depression in the Elderly

To investigate a possible relationship between plasma levels of trazodone and its clinical antidepressant effects, 11 elderly depressed patients underwent a 5-week treatment with 150 mg/day trazodone in three oral administrations. Clinical antidepressant response was assessed with two different clinical improvement criteria and plasma trazodone concentrations were determined by high-performance liquid chromatography. A significant correlation was found between steady-state plasma trazodone levels and its antidepressant efficacy, but not between plasma drug levels and the incidence of side effects. Moreover, the steady-state plasma trazodone concentration of 650 ng/ml was identified as threshold value for a greater occurrence of good antidepressant responses.

Plasma Trazodone Concentrations and Clinical Response in Elderly Depressed Patients

Steady-state plasma levels of trazodone were determined by HPLC in 11 elderly depressed patients who underwent a 5-week pharmacological treatment with 150 mg/day trazodone in three oral administrations. Clinical antidepressant response, assessed with three different clinical improvement criteria, was significantly correlated with steady-state plasma trazodone concentrations. Moreover, the steady-state plasma trazodone concentration of 650 ng/ml was identified as the threshold value for a good antidepressant response. No correlation was found between the occurrence of side effects and plasma levels of trazodone.

Determination of trazodone in serum by instrumental thin-layer chromatography.

A simple and specific method for trazodone that uses high-performance thin-layer chromatography (TLC) plates for chromatography and the Camag TLC Scanner for fluorescence-reflectance measurements is described. The quantitative method employs quinidine as an internal standard and the calibration line is linear between 0.2 and 2.0 mg/L serum, the usual range encountered in patients treated with the drug. Replicate analyses of single serum specimens demonstrated reproducibility of better than +/- 3% coefficient of variation for concentrations of trazodone in the midrange of the test line.

Voltammetric and Chromatographic Assay of Trazodone

Abstract Trazodone, a triazolopyridine derivative with antidepressant activity, is irreversibly oxidized in two steps in a large range of scan rates. The first peak shows a linear dependence on trazodone concentration. This behaviour is used for analytical purposes in determining trazodone concentrations in commercial preparations. An original alternative gas-liquid chromatographic method is also developed. Comparison of the chromatographic with voltammetric methods shows that a) both are sensitive enough to be applied to single tablet assays; b) the major advantage of the voltammetric method for analytical purposes lies in the rapid determination of the trazodone content in tablets. Preparation of the samples is easy and no extraction procedure is required.

Trazodone and m-chlorophenylpiperazine : Concentration in brain and receptor activity in regions in the brain associated with anxiety

Trazodone, its active metabolite 1-( m-chlorophenyl)piperazine ( mCPP) and two isomers of mCPP were tested for affinity to the binding sites for [ 3H]flunitrazepam ([ 3H]FLU) and [ 3 H]p- aminoclonidine ([ 3 H]p AC) in the frontal cortex, amygdala and hippocampus of the rat. When tested at the binding site for [ 3H]flunitrazepam, trazodone showed an average IC 50 of 1.7 mM in all three regions of the brain while mCPP yielded an average IC 50 of 0.36 mM. These same two compounds, when tested at the binding site for [ 3 H]p- aminoclonidine , resulted in an average IC 50 of 4.5μM for trazodone and 0.6 μM for mCPP. When plasma values of trazodone and mCPP in the rat were similar to those obtained in patients given therapeutic doses, the concentrations of trazodone were found to be between 6 and 7 μM and between 2 and 3 μM for mCPP in the same brain regions of the brain used in the binding assays. Thus, a sufficient concentration of trazodone and m CPP can accumulate in brain tissue to displace approx. 50% of the [ 3 H]p- aminoclonidine from its binding site but very little [ 3H]flunitrazepam from its binding site. These results, combined with the reported anxiolytie effects of the alpha-2 agonist, clonidine and the noradrenergic hyperactivity theory of anxiety, indicate that the mechanism of the anxiolytic activity of trazodone, may be a direct action on the central alpha-2 binding site.

Comparative bioavailability of trazodone formulations using stable isotope methodology.

The bioavailability of trazodone, a new antidepressant, from 50 mg dividose (A) or film-sealed (B) tablets relative to an oral solution was determined in six healthy male subjects using 50 mg of D4-trazodone as a stable isotope labelled standard. Concentrations of trazodone and D4-trazodone were measured by GCMS. The pharmacokinetics of trazodone and D4-trazodone were identical indicating no isotope effect. For formulation A, B and solution, the relative (trazodone/D4-trazodone) Cmax values were 0.84 +/- 0.09, 0.90 +/- 0.05 and 1.05 +/- 0.04. The relative bioequivalence of the dosage formed with a power of 85% (power by conventional ANOVA was 54%). Among subjects % relative standard deviations (RSD) for the D4-trazodone AUC values, a measure of intra-subject variability, were 6 to 38% while the % RSDs by period, a measure of inter-subject variability, were 26 to 55%.

Liquid-chromatographic determination of two antidepressants, trazodone and mianserin, in plasma.

Plasma containing trazodone or mianserin was extracted. The organic phase containing trazodone was evaporated and the residue was reconstituted in dilute acid. Mianserin was back-extracted from the organic phase with dilute acid. Both drugs were chromatographed on mu Bondapak C18 columns, with phosphate/acetonitrile as the mobile phase. Peak-height ratios of drug/internal standard were linearly correlated with concentrations between 25 and 2000 micrograms/L for trazodone, and between 25 and 200 micrograms/L for mianserin, with respective between-run CVs of 4.7% and 7.6%. Detection limits were 5 ng. Of some common drugs and metabolites examined, nortriptyline co-elutes with the internal standard used in the trazodone assay, while flurazepam co-elutes with mianserin. Concentrations of trazodone in 26 patients ranged from 73 to 1678 micrograms/L. For two geriatric patients, concentrations were about 2000 micrograms/L. For two overdose patients, they were about 5000 micrograms/L. The concentration of mianserin was 27 micrograms/L for a volunteer treated with a single 40-mg oral dose.

Plasma concentrations of trazodone and 1-(3-chlorophenyl)piperazine in man after a single oral dose of trazodone.

Plasma concentrations of trazodone and 1-(3-chlorophenyl)piperazine in man after a single oral dose of trazodone.