Pharmacokinetics of Trazodone in Hispaniolan Parrots (Amazona ventralis).

The objective of this study was to establish the pharmacokinetics of a single oral dose of trazodone in the Hispaniolan Amazon parrot (Amazona ventralis). Trazodone is a selective serotonin antagonist and reuptake inhibitor used commonly in both human and veterinary medicine as an antidepressant behavioral modification medicine. A single oral dose of compounded trazodone hydrochloride solution (20 mg/mL) at 50 mg/kg was administered to a total of 7 healthy adult Hispaniolan Amazon parrots. The 7 healthy adult parrots ranged in age from 10 to 15 years and weighed 228 to 323g. Blood was collected at baseline (2 weeks before study) and at 1, 2, 4, 6, 10, and 14 hours post-drug administration. Plasma concentrations of both trazodone and its active metabolite m-chlorophenylpiperazine (mCPP) were measured via liquid chromatography tandem mass spectrometry. Noncompartmental pharmacokinetic analysis was completed. The half-life (t1/2) ± SD of trazodone for the Hispaniolan parrots was 1.89 ± 0.49 hours, and the t1/2 ± SD of mCPP metabolite was 1.9 ± 0.55 hours. Maximum serum drug concentrations, or Cmax (ng/mL), were 738.3 ± 285.3 for trazodone. Times to achieve Cmax (hours) for trazadone and the mCPP metabolite were 1 hour and 2 hours postdosing, respectively. While this study did not establish the behavioral effects of trazodone, no adverse side effects were observed throughout the 48-hour period following drug administration and blood collection. Our results indicate that the oral administration of a 50-mg/kg single dose of trazodone to Hispaniolan parrots may be considered a safe dose. Plasma concentrations are comparable to previously published values in humans, dogs, horses, and pigeons (Columba livia domestica) for up to 14 hours following dosing. This study indicates that further studies are needed to establish the pharmacodynamics and the efficacy of trazodone in the medical management of behavioral problems in psittacine species.

PHARMACOKINETICS AND CLINICAL EFFECTS OF A SINGLE ORAL DOSE OF TRAZODONE IN THE DOMESTIC GOAT (CAPRA HIRCUS) AS A MODEL FOR WILD RUMINANTS.

Trazodone is an antianxiety medication commonly used in human and veterinary medicine. Stress-related trauma is the leading cause of morbidity and mortality in wild ruminant species. Trazodone could reduce stress and allow safer capture and handling, thus having a positive effect on their welfare. The objective of this study was to describe the clinical effects and pharmacokinetic profile of an oral dose of trazodone in domestic goats (Capra hircus) as a model for wild ruminants. A pilot study using ethograms and accelerometers identified an oral dose of 10 mg/kg as optimal to reduce activity levels. This dose resulted in a 502% increase in time spent sleeping (P=0.0016) and a 623% increase in time spent lying down (P=0.01). Additionally, there were reductions of 72% in time spent grooming (P=0.02), 49% in time spent moving (P=0.01), and 87% in time spent observing (P=0.0002). Activity levels were significantly decreased by 31% for 4 hr following administration (P=0.049). There were no observed adverse effects. Time spent eating or ruminating was not affected by trazodone administration (P > 0.05). The pharmacokinetics of trazodone following a single oral dose of 10 mg/kg in 7 goats was assessed. All animals achieved plasma concentrations over 130 ng/ml, a level considered therapeutic in humans and dogs, for a mean of 6.4 ± 5.0 hr. Mean terminal half-life was 10.55 ± 6.80 hr. All goats achieved maximum concentration within 5-15 min and still had detectable plasma levels at 24 hr. Trazodone appears promising to decrease stress in exotic ruminant species. Further research is warranted to establish its efficacy in other ruminant species and clinical situations.

Physiologically Based Dissolution Testing in a Drug Development Process-a Case Study of a Successful Application in a Bioequivalence Study of Trazodone ER Formulations Under Fed Conditions.

Development of generic extended-release (ER) formulations is challenging. Especially under fed conditions, the risk of failure in bioequivalence trials is high because of long gastric residence times and susceptibility to food effects. We describe the development of a generic trazodone ER formulation that was aided with a biorelevant dissolution evaluation. Trazodone hydrochloride 300-mg monolithic matrix tablets were dissolved both in USP and EMA compliant conditions and in the StressTest device that simulated both physicochemical and mechanical conditions of the gastrointestinal passage. The final formulation was tested against the originator, Trittico XR 300 mg, in a randomized cross-over bioequivalence trial with 44 healthy volunteers, in agreement with EMA guidelines. Initially developed formulations dissolved trazodone similarly to the originator under standard conditions (f2 factor above 50), but their dissolution kinetics differed significantly in the biorelevant tests. The formulation was optimized by the addition of low-viscosity hypromellose and mannitol. The final formulation was approved for the bioequivalence trial. Calculated Cmax were 1.92 ± 0.77 and 1.92 ± 0.63 [µg/mL], AUC0-t were 27.46 ± 8.39 and 29.96 ± 9.09 [µg∙h/mL], and AUC0-∞ were 28.22 ± 8.91 and 30.82 ± 9.41 [µg∙h/mL] for the originator and test formulations, respectively. The 90% confidence intervals of all primary pharmacokinetic parameters fell within the 80-125% range. In summary, biorelevant dissolution tests supported successful development of a generic trazodone ER formulation pharmaceutically equivalent with the originator under fed conditions. Employment of biorelevant dissolution tests may decrease the risk of failure in bioequivalence trials of ER formulations.

Pharmacokinetics of trazodone sustained-release tablets in healthy subjects: Three open-label, randomized crossover studies
.

OBJECTIVE: To characterize the pharmacokinetics of trazodone hydrochloride (HCl) sustained-release tablets (TSR) and trazodone immediate-release formulation (TIR) and investigate the effects of food on the pharmacokinetics of the drug in healthy subjects. MATERIALS AND METHODS: Three open-label, randomized crossover trials of single-dose, multiple-dose, and food-drug interaction testing were conducted. A validated high-performance liquid chromatography-fluorescence method was used to measure the plasma concentration of trazodone, and a non-compartment model was used to obtain the pharmacokinetic parameters. AUC and Cmax dose proportionality were analyzed using a power model. RESULTS: TSR lacked dose proportionality over a dose range of 25 - 150 mg. In the food-drug interaction study, no significant changes in the pharmacokinetic parameters of the drug under the fed conditions were observed. Multiple dosage of TSR and TIR reached steady state after 7 days, with no accumulation phenomenon observed. The peak time and peak concentrations of TSR were significantly longer and lower, respectively, than those of TIR. CONCLUSION: TSR showed clear sustained-release characteristics, and food exhibited no significant effects on the pharmacokinetic parameters of trazodone. TSR and TIR reached steady state levels after 7 consecutive days of administration, with no accumulation phenomenon observed.

Pharmacokinetics, pharmacodynamics and clinical use of trazodone and its active metabolite m-chlorophenylpiperazine in the horse.

Trazodone is a serotonin receptor antagonist and reuptake inhibitor used extensively as an anxiolytic in human and small animal veterinary medicine. The aims of this study were to determine the pharmacokinetics of oral trazodone in experimental horses and to evaluate the effect of oral trazodone in clinical horses. Six experimental horses were administered trazodone at 7.5 or 10 mg/kg. Plasma concentrations of trazodone and its metabolite (m-CPP) were determined via UPLC-MS/MS. Noncompartmental pharmacokinetic analysis, sedation and ataxia scores were determined. Trazodone was rapidly absorbed after oral administration with a maximum concentration of 2.5-4.1 µg/ml and half-life of the terminal phase of approximately 7 hr. The metabolite was present at low levels in all horses, representing only 2.5% of the total area under the curve. In experimental horses, concentration-dependent sedation and ataxia were noted, lasting up to 12 hr. For clinical cases, medical records of horses treated with trazodone for various abnormal behaviours were reviewed and data were summarized. Trazodone was successful in modifying behavioural problems to some degree in 17 of 18 clinical cases. Tolerance and subsequent lack of drug effect occurred in two of 18 clinical cases following 14 or 21 days of use. In both populations of horses, adverse effects attributed to trazodone include oversedation, muscle fasciculations and transient arrhythmias.

Development, optimization and ex-vivo evaluation of a transdermal formulation containing trazodone.

Trazodone is a triazolpyridine derivative approved for the treatment of depression, and currently marketed as oral formulations. The transdermal administration of this drug could reduce side effects, related to peak plasma concentration, and improve patient adherence due to a reduced administration frequency. The aims of this work were: (a) the evaluation of the effect of pH vehicle and permeation enhancers on trazodone permeability across porcine skin ex-vivo; (b) the development and optimization of a transdermal drug delivery system containing trazodone hydrochloride. From the results obtained, it was found that the effect of pH of the vehicle on the permeation of trazodone across the skin is quite complex, because it influences both solubility and partitioning and that the presence of fatty acids in the vehicle has a notable effect on permeation (the enhancement factor obtained was approx. 100). For both the fatty acid selected (oleic and lauric) a parabolic relationship between the transdermal flux and the concentration was found, with an optimum activity in the range 2-3 %. In the second part of the work, different patches were prepared and tested ex-vivo. Overall, the results obtained seem to highlight that drug loading, rather than the components of the adhesive matrix, plays the most relevant role for the permeation of trazodone. The addition of lauric acid, which produced a considerable enhancement in solution, was not effective when included in the patch. The obtained data are promising although probably not clinically relevant for the treatment of depression, but might be interesting for the treatment of insomnia and anxiety disorder, which require much lower doses.

Influence of trazodone on the pharmacodynamics and pharmacokinetics of pioglitazone.

BACKGROUND: These days, poly pharmacy is very common for the treatment of multiple diseases and majority of drugs were metabolized with CYP 450 enzymes. Diabetes mellitus is such a disorder, which requires continuous therapy for the control of blood glucose concentration. Depression was quite common in diabetic patients. Therefore, multiple drugs required to treat diabetes mellitus and depression. Simultaneous administration of these drugs leads to drug interaction. Pioglitazone and trazodone metabolized by CYP3A4 enzymes which may lead to potential drug interaction. OBJECTIVES: This study aimed to find the influence of trazodone on the pharmacokinetics & pharmacodynamics of pioglitazone in normal & diabetic rats, also on rabbits and subsequently effectiveness and safety of the combination was evaluated. METHODS AND MATERIAL: Blood glucose concentration was determined by Glucose oxidase/peroxidase method in normal and diabetic rats. Diabetes was induced with Streptozotocin at a dose of 55 mg/kg body weight. Serum pioglitazone concentration was estimated by high performance liquid chromatography method for pharmacokinetic data. The values were expressed as Mean ± Standard Error Mean (SEM), GraphPad Prism 3.0 (San Diego, California, USA) software was used to express the data. Student's paired 't' test was used to determine the significance. RESULTS: Pioglitazone produces hypoglycaemia in normal rats with a maximum decrease of 36.78 % ± 0.81 at 3 hours interval and anti-hyperglycaemic activity in diabetic rats with maximum reduction of 45.13 % ± 1.52 at 2 hours interval. Trazodone altered the pharmacokinetics of pioglitazone and improved the pioglitazone hypoglycaemic effect. CONCLUSION: Trazodone apparently produced pharmacokinetic interaction with pioglitazone which might be by attenuating the metabolism of pioglitazone. Therefore, care should be taken in simultaneous therapy with pioglitazone and trazodone.

Safety, tolerability, and pharmacokinetics of once-daily trazodone extended-release caplets in healthy subjects.

OBJECTIVE: To characterize the pharmacokinetics, safety, and tolerability of an extended-release formulation of trazodone hydrochloride (HCl), Trazodone Contramid® Once-a-Day (TzCOAD) developed as scored 150-mg and 300-mg caplets for oncedaily administration. METHODS: Relative bioavailability studies compared the pharmacokinetics of TzCOAD and trazodone immediate-release (TzIR) tablets following single- and multiple-dose administration. In addition, the effect of food on the pharmacokinetics of TzCOAD was assessed. RESULTS: After single-dose administration of 300 mg TzCOAD, trazodone AUC and C(max) were approximately 20% and 60% lower, respectively, than for TzIR 100-mg tablets administered as 3 doses, 8 h apart. After multipledose administration of 300 mg daily for 7 days, TzCOAD given once daily and TzIR given 3 times a day were equivalent with respect to AUC, while C(max) was 43% lower for TzCOAD. Trazodone AUC following single-dose administration of TzCOAD was similar to AUC at steady state, suggesting that steady-state exposure can be predicted from single-dose data. When TzCOAD was taken shortly after ingestion of a high-fat meal, C(max) increased 86% compared with fasting conditions. However, AUC and t(max) were not affected by food. CONCLUSION: Administration of TzCOAD 300 mg once daily provides equivalent steady-state exposure to, with a lower C(max) than, TzIR 100 mg given 3 times a day. A high-fat meal results in an increase in C(max), but there is no substantial effect on AUC.

Prolonged delirium after quetiapine overdose.

Quetiapine is an atypical antipsychotic agent increasingly used to treat schizophrenia and bipolar disorder in pediatric patients. Few published data exist concerning quetiapine's effects in therapeutic settings or short-term overdose in pediatric and adolescent populations. In this report, we describe a 15-year-old adolescent girl who experienced continued delirium 5 days after an overdose of quetiapine, trazodone, and clonidine. The patient initially presented with sedation and stable vital signs. After 3 days of gradual improvement, she experienced episodes of delirium coinciding with an increase in resting heart rate. On the basis of suspicion for quetiapine-associated antimuscarinic effects, the patient was administered intravenously with physostigmine on the fifth day after ingestion. Treatment resulted in a brief resolution of symptoms. Serum quetiapine levels measured 1 day and 5 days after ingestion were 3400 and 4800 ng/mL, respectively. The use of physostigmine and interpretation of serum levels are discussed further.

Estimation of an Appropriate Dose of Trazodone for Pediatric Insomnia and the Potential for a Trazodone-Atomoxetine Interaction.

There is a paucity of clinical trials for the treatment of pediatric insomnia. This study was designed to predict the doses of trazodone to guide dosing in a clinical trial for pediatric insomnia using physiologically-based pharmacokinetic (PBPK) modeling. Data on the pharmacokinetics of trazodone in children are currently lacking. The interaction potential between trazodone and atomoxetine was also predicted. Doses predicted in the following age groups, with exposures corresponding to adult dosages of 30, 75, and 150 mg once a day (q.d.), respectively, were: (i) 2- to 6-year-old group, doses of 0.35, 0.8, and 1.6 mg/kg q.d.; (ii) >6- to 12-year-old group, doses of 0.4, 1.0, and 1.9 mg/kg q.d.; (iii) >12- to 17-year-old group, doses of 0.4, 1.1, and 2.1 mg/kg q.d. An interaction between trazodone and atomoxetine was predicted to be unlikely. Clinical trials based on the aforementioned predicted dosing are currently in progress, and pharmacokinetic data obtained will enable further refinement of the PBPK models.

[Personalized treatment of depression phenotypes: role of trazodone in depression with insomnia]. / Trattamento personalizzato dei fenotipi di depressione: ruolo del trazodone nella depressione con insonnia.

AIM: This paper completes a series of three manuscripts on the clinically relevant evidence of the use of trazodone in major depressive disorder. The first paper provided general clinical guidance on the use of trazodone in major depressive disorder. The second paper evaluated the different clinical scenarios in which trazodone prolonged-release or trazodone Contramid® once-a-day may be more indicated. This third and last paper evaluates the clinically relevant evidence about the use of trazodone in major depressive disorder (MDD) with insomnia. METHODS: Medline and Cochrane Library searches were performed using the keywords 'trazodone' AND 'depression' AND 'insomnia', to identify the most relevant literature on the use of trazodone in patients with MDD and insomnia. European and the United States prescribing information was reviewed as well. More weight was given to the information that was deemed as most relevant for daily clinical practice. RESULTS: Trazodone is an effective medication for patients with MDD and insomnia. DISCUSSION: Trazodone is efficacious for the treatment of a broad array of depressive symptoms and is particularly useful for patients presenting with insomnia as one of the symptoms of depression. CONCLUSIONS: Trazodone improves sleep and depression and is particularly helpful for patients whose symptoms of depression include insomnia.

Trazodone Loaded Lipid Core Poly (ε-caprolactone) Nanocapsules: Development, Characterization and in Vivo Antidepressant Effect Evaluation.

Trazodone hydrochloride (TRH) is a lipophilic drug which is used effectively as an antidepressant. Its poor solubility and short half-life represent an obstacle for its successful use. Nanocapsules with biodegradable polymeric shell are successful drug delivery systems for controlling the release of drugs. To enhance the entrapment of lipophilic drugs, oils can be added forming a lipophilic core in which the drug is more soluble. The aim of this study was to enhance the efficacy of TRH and prolong its action by formulating it into lipid core polymeric shell nanocapsules. Nanocapules were prepared using nanoprecipitation technique. All prepared formulations were in nano size range and negatively charged. The TRH entrapment efficiency (EE%) in lipid core nanocapsules was up to 74.8 ± 0.5% when using Labrafac lipophile as a lipid core compared to only 55.7 ± 0.9% in lipid free polymeric nanospheres. Controlled TRH release was achieved for all prepared formulations. Forced swim test results indicated the significant enhancement of antidepressant effect of the selected TRH loaded Labrafac lipophile core nanocapsules formulation compared to control and TRH dispersion in phosphate buffer. It is concluded that lipid core nanocapsules is a promising carrier for the enhancement of TRH efficacy.

Effect of 3 Single Doses of Trazodone on QTc Interval in Healthy Subjects.

This study evaluated the effect of 3 doses of a trazodone hydrochloride 6% oral drops solution on the QT interval of healthy volunteers. Subjects were randomly assigned to receive a single dose of trazodone 20 mg, 60 mg, and 140 mg, moxifloxacin 400 mg, and trazodone-matched placebo in 5 periods separated by 7-day washouts, according to a double-blind, crossover study design. Subjects were monitored continuously, and triplicate ECGs were extracted from baseline (predose) until 24 hours postdose. Blood samples for trazodone and moxifloxacin analyses were collected at the same time points. The concentration-QTc relationship assessed on placebo-adjusted change from baseline for Fridericia-corrected QT (ΔΔQTcF) was the primary end point. ΔΔQTcF values of 4.5, 12.3, and 19.8 ms for the 20-, 60-, and 140-mg doses were observed at the corresponding trazodone peak plasma concentrations. The upper bound of the 90%CI exceeded 10 ms for the 60- and the 140-mg doses. Time-matched analysis results were in line with these findings. No significant trazodone effect on heart rate or PR or QRS intervals and no clinically significant new morphological changes were present. In this moxifloxacin-validated ECG trial, trazodone had a modest, dose-dependent effect on cardiac repolarization, with no QTc prolongation observed with the 20-mg dose and an effect exceeding the values set in E14 guideline with the 60- and 140-mg doses. The effect on cardiac repolarization is unlikely to represent a clinical risk for ventricular proarrhythmia, but caution should be used with concomitant use of other medications that prolong QT or increase trazodone exposure.

Determination of the pharmacokinetics of a single oral dose of trazodone and its effect on the activity level of domestic pigeons (Columba livia).

OBJECTIVE: To determine the pharmacokinetics of a single oral dose of trazodone and its effect on the activity of domestic pigeons (Columba livia). ANIMALS: 6 healthy adult male domestic pigeons. PROCEDURES: During the first of 3 experiments, birds received orally administered trazodone at doses ranging from 3 to 30 mg/kg to determine the dose for subsequent experiments. During the second experiment, each bird received 1 dose of trazodone (30 mg/kg, PO). Blood was collected for determination of plasma trazodone concentration before and at predetermined times for 24 hours after drug administration. Pharmacokinetic parameters were calculated by noncompartmental analysis. During experiment 3, birds were instrumented with ultralightweight accelerometers and received orally administered trazodone (30 mg/kg) or an equal volume of water twice at a 48-hour interval. Activity of birds was monitored for 24 hours after administration of each treatment. RESULTS: No adverse effects were observed. Mean ± SD terminal half-life of trazodone was 5.65 ± 1.75 hours. Plasma trazodone concentrations remained > 0.130 µg/mL for approximately 20 hours. Trazodone did not affect the activity of birds during the first 2 and 15 hours after administration. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that oral administration of 1 dose (30 mg/kg) of trazodone to healthy pigeons was safe and resulted in plasma drug concentrations that were similar to those considered therapeutic in humans and dogs for up to 20 hours. Further research is necessary to characterize the pharmacokinetics for repeated doses as well as the clinical effects of trazodone in birds with behavior problems.

High throughput and sensitive determination of trazodone and its primary metabolite, m-chlorophenylpiperazine, in human plasma by liquid chromatography-tandem mass spectrometry.

A precise, sensitive and high throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of trazodone (TRZ) and its primary metabolite, m-chlorophenylpiperazine (mCPP), in human plasma was developed and validated. The analytes and the internal standard-nefazodone were extracted from 500 microL aliquots of human plasma via liquid-liquid extraction in n-hexane. Chromatographic separation was achieved in a run time of 2.5 min on a Betabasic cyano column (100 mm x 2.1 mm, 5 microm) under isocratic conditions. Detection of analytes and IS was done by tandem mass spectrometry, operating in positive ion and multiple reaction monitoring (MRM) acquisition mode. The protonated precursor to product ion transitions monitored for TRZ, mCPP and IS were m/z 372.2-->176.2, 197.2-->118.1 and 470.5-->274.6 respectively. The method was fully validated for its sensitivity, selectivity, accuracy and precision, matrix effect, stability study and dilution integrity. A linear dynamic range of 10.0-3000.0 ng/mL for TRZ and 0.2-60.0 ng/mL for mCPP was evaluated with mean correlation coefficient (r) of 0.9986 and 0.9990 respectively. The intra-batch and inter-batch precision (%CV) across five validation runs (LLOQ, lower limit of quantitation; LQC, low quality control; MQC, middle quality control; HQC, high quality control and ULOQ, upper limit of quantitation) was < or =8.4% for both the analytes. The method was successfully applied to a bioequivalence study of 100mg trazodone tablet formulation in 36 healthy Indian male subjects under fasting and fed conditions.

Ex vivo and in vivo evaluation of transdermal formulation of trazodone hydrochloride.

The aim of the present investigation is to evaluate the biopharmaceutical behaviors of the matrix patch containing trazodone hydrochloride (TZN) following transdermal administration in rabbits. The ex vivo skin permeation study was performed using Keshary-Chien glass diffusion cell and mouse epidermis with intact stratum corneum as membrane. The phosphate buffer of pH 7.4 was used as receptor solution at 37 degrees C. TZN patch was applied to the inner pinna skin of the rabbit. TZN transdermal absorption from patch was compared to that from peroral TZN solution in rabbit. A steady-state skin permeation rate of 134.09 +/- 2.49 microg/cm2/h was achieved from the matrix patch across mouse epidermis after an initial lag time of approximately 3.5 h. The steady-state transdermal TZN concentration of 2.3 microg/mL was achieved in rabbit from the matrix patch after an initial lag time of approximately 2 h. The Cmax of peroral TZN solution was calculated to be 5.84 microg/mL at a Tmax of 2 h indicating its rapid absorption compared to the transdermal administration with a Tmax of 5 h. The ex vivo and in vivo biopharmaceutical parameters were in good agreement with respect to steady-state plasma TZN concentration and lag time. The plasma level of TZN following transdermal application could be maintained for 24 h. The transdermal dose achieved a much higher steady-state blood concentration in rabbit compared with the effective blood concentration in human. The observed steady-state blood concentration may appear to be within the expected therapeutic range in human with a higher clearance value compared to that in rabbit.

Pharmacogenetics of trazodone in healthy volunteers: association with pharmacokinetics, pharmacodynamics and safety.

AIM: The aim was to evaluate the effect of polymorphisms in metabolizing enzymes and transporters on the pharmacokinetics, pharmacodynamics and adverse effects of trazodone in healthy volunteers. MATERIALS & METHODS: 36 healthy volunteers receiving a single 100-mg oral dose of trazodone were genotyped for 11 variants in CYP3A4, CYP3A5, CYP2D6 and ABCB1 by real-time PCR. Plasma concentrations were measured using liquid chromatography-tandem mass spectrometry method. RESULTS & CONCLUSION: Sex affected the pharmacokinetics of trazodone with higher clearance in women. Polymorphisms in ABCB1, but not in CYP3A or CYP2D6, influenced trazodone pharmacokinetics. Trazodone decreased blood pressure and prolonged the corrected QT interval interval. CYP2D6 and ABCB1 polymorphisms were associated with the incidence of dizziness and prolonged corrected QT interval, respectively. Subjects with adverse drug reactions had lower concentrations of trazodone suggesting its metabolite (m-chlorophenylpiperazine) could be responsible for these effects.

Pharmacokinetics and selected pharmacodynamics of trazodone following intravenous and oral administration to horses undergoing fitness training.

OBJECTIVE To measure concentrations of trazodone and its major metabolite in plasma and urine after administration to healthy horses and concurrently assess selected physiologic and behavioral effects of the drug. ANIMALS 11 Thoroughbred horses enrolled in a fitness training program. PROCEDURES In a pilot investigation, 4 horses received trazodone IV (n = 2) or orally (2) to select a dose for the full study; 1 horse received a vehicle control treatment IV. For the full study, trazodone was initially administered IV (1.5 mg/kg) to 6 horses and subsequently given orally (4 mg/kg), with a 5-week washout period between treatments. Blood and urine samples were collected prior to drug administration and at multiple time points up to 48 hours afterward. Samples were analyzed for trazodone and metabolite concentrations, and pharmacokinetic parameters were determined; plasma drug concentrations following IV administration best fit a 3-compartment model. Behavioral and physiologic effects were assessed. RESULTS After IV administration, total clearance of trazodone was 6.85 ± 2.80 mL/min/kg, volume of distribution at steady state was 1.06 ± 0.07 L/kg, and elimination half-life was 8.58 ± 1.88 hours. Terminal phase half-life was 7.11 ± 1.70 hours after oral administration. Horses had signs of aggression and excitation, tremors, and ataxia at the highest IV dose (2 mg/kg) in the pilot investigation. After IV drug administration in the full study (1.5 mg/kg), horses were ataxic and had tremors; sedation was evident after oral administration. CONCLUSIONS AND CLINICAL RELEVANCE Administration of trazodone to horses elicited a wide range of effects. Additional study is warranted before clinical use of trazodone in horses can be recommended.

131I-trazodone: preparation, quality control and in vivo biodistribution study by intranasal and intravenous routes as a hopeful brain imaging radiopharmaceutical.

OBJECTIVES: The preparation of 131I-trazodone hydrochloride and its biological evaluation as a promising brain imaging radiopharmaceutical using two routes of administration. MATERIAL AND METHODS: Trazodone (TZ) was radiolabelled with 131I using direct electrophilic substitution, and different factors affecting labelling yield were studied. Quality control of 131I-TZ was carried out using ascending paper chromatography, paper electrophoresis, and high pressure liquid chromatography (HPLC). In vivo biodistribution of 131I-TZ was evaluated in Swiss albino mice using 3 methods: intravenous 131I-TZ solution (IVS), intranasal 131I-TZ solution (INS), and intranasal 131I-TZ microemulsion (INME). RESULTS: Optimum labelling yield of 91.23±2.12% was obtained with in vitro stability of 131I-TZ up to 6h at room temperature. The biodistribution results showed a notably higher and sustained brain uptake for INME compared to IVS and INS at all time intervals. In addition, heart and blood uptake levels for INME were lower than those for IV solution which, in turn, could decrease the systemic side effects of trazodone. Also, the 131I-trazodone INME brain uptake of 6.7±0.5%ID/g was higher than that of 99mTc-ECD and 99mTc-HMPAO (radiopharmaceuticals currently used for brain imaging). CONCLUSION: 131/123I-trazodone formulated as INME could be used as a promising radiopharmaceutical for brain imaging.

Effect of different terpene-containing essential oils on percutaneous absorption of trazodone hydrochloride through mouse epidermis.

The aim of our study was to investigate the enhancing effect of several essential oils in the percutaneous absorption of trazodone hydrochloride (TZN). For this purpose, fennel oil, eucalyptus oil, citronella oil, and mentha oil were applied on the skin membrane in three different ways: included in the transdermal device, as a pretreatment, or both. To investigate the effect of penetration enhancers used in this study on the percutaneous absorption of TZN through mouse epidermis, Keshary-Chien diffusion cells were employed. The receptor phase was constantly stirring saline phosphate buffer of pH 7.4 at 37 +/- 1 degrees C. Results showed that pretreatment of skin with essential oils increases the flux values of TZN compared with the values obtained when the same essential oils were included in the transdermal devices. The percutaneous penetration flux for TZN was increased with skin pretreatment by 10% essential oils in the following order: fennel oil > eucalyptus oil > citronella oil > mentha oil. The amount of TZN retained in the skin after pretreatment with essential oils was found to be very similar in all cases and much higher than in the experiments without skin pretreatment.