• View in gallery
    Figure 1—

    Calibration curve for quantification of trazodone in the plasma of domestic pigeons (Columba livia) by HPLC-MS-MS. Blank domestic pigeon plasma was spiked with a trazodone standard at concentrations ranging from 0.05 to 10.0 μg/mL and a constant concentration (1.0 μg/mL) of trazodone-d6 (internal standard). The trazodone-to-trazo-done-d6 peak area ratio was calculated. Each calibration curve consisted of a double blank (plasma sample without analyte [trazodone] and without the internal standard), a zero standard (plasma sample without analyte but with internal standard) and 6 calibration points. Linear regression (weighted, 1/concentration) provided the best fit between the trazodone concentration measured by the instrument and the known trazodone concentration.

  • View in gallery
    Figure 2—

    Mean ± SD plasma trazodone concentration over time following oral administration of a single dose (30 mg/kg) of the drug to 6 healthy adult male domestic pigeons. The shaded area represents the plasma trazodone concentration range (0.13 to 2.2 μg/mL) that is considered therapeutic for humans. The dashed line represents the line of best fit for the data. The dotted line represents the point at which the line of best fit for the data decreased to below the lower limit of the therapeutic trazodone concentration range for humans.

  • View in gallery
    Figure 3—

    Mean ± SD activity count for 6 healthy adult male domestic pigeons before (baseline; white bars) and during the first 2 and 15 hours after oral administration of trazodone (30 mg/kg; black bars) or an equal volume of water (gray bars) twice at 48-hour intervals during both phases 1 and 2 of the accelerometry experiment. Each bird was instrumented with an ultralightweight accelerometer throughout the experiment, and activity was assessed in 2-minute epochs. Baseline data were acquired over a period of 3 days prior to initiation of phase 1 during which the birds were not handled. The baseline activity count represents the mean activity count for birds over the same hours during each day of the baseline period as those for which the activity counts were recorded after the respective treatments.a,b Within each posttreatment interval, means denoted with different lowercase letters differ significantly (P < 0.05).

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

Marion R. DesmarchelierDépartement de Sciences Cliniques, Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, QC J2S 2M2, Canada.

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Francis BeaudryGroupe de Recherche en Pharmacologie Animale du Québec (GREPAQ), Département de Biomédecine Vétérinaire, Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, QC J2S 2M2, Canada.

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Shannon T. FerrellZoo de Granby, 1050 Blvd David-Bouchard N, Granby, QC J2G 5P3, Canada.

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Diane FrankDépartement de Sciences Cliniques, Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, QC J2S 2M2, Canada.

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Abstract

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.

Abstract

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.

Pet birds commonly develop behavior problems, with as many as 71% of pet-bird owners reporting that their birds display abnormal behavior and 36% of those owners considering the abnormal behavior problematic.1 Behavior modification associated with the appropriate use of antianxiety drugs is recommended to manage behavior problems in various species. Unfortunately, there is a paucity of objective data regarding the use of psychotropic drugs in birds. Various sedatives and antidepressants are empirically used to treat behavior problems in pet birds.2 The pharmacokinetics of amitriptyline3 and paroxetine4 have been evaluated in parrots, as has the clinical efficacy of clomipramine for treatment of feather-damaging behavior.5,6

The antidepressant trazodone is considered a useful dose-dependent multifunctional psychotropic drug in human psychopharmacology and is categorized as a serotonin antagonist and reuptake inhibitor.7,8 It has a high affinity for and exerts antagonist activity on the 5-hydroxytryptamine 2A receptor subtype and provides fairly weak inhibition of the serotonin transporter 5-HT.9 Trazodone also blocks α1, and to a lesser extent α2, adrenoreceptors and histamine H1 and 5-HT2C receptors.7,10 It is considered a safe and effective antidepressant and is associated with a low incidence of adverse effects such as anxiety, insomnia, and sexual dysfunction.7,11,12

In human medicine, trazodone is used to manage a wide variety of conditions including insomnia, depression, bulimia, and fibromyalgia.9,13 In veterinary medicine, trazodone has been used with increasing frequency over the last decade, and the pharmacokinetics of the drug has been evaluated in dogs14 and horses.15 In dogs, trazodone is commonly used to decrease anxiety and stress during the perioperative period, treat thunderstorm and noise phobias, and manage separation and other anxiety disorders.16–19 Results of 2 studies suggest that trazodone can be administered to cats to induce sedation20 and decrease transport- and examination-related anxiety.21 Given that both pet and wild birds frequently display stress-related behavior during transport, hospitalization, and examination and the fact that anxiety disorders are commonly reported in parrots, trazodone might be a useful additional tool for avian practitioners and behaviorists. In 2 studies, trazodone did not appear to have any antidepressant or anxiolytic effects in young domestic fowl22 or pigeons.23 However, to our knowledge, clinical use of trazodone has not been described for any avian species.

The objective of the study reported here was to determine the pharmacokinetics of a single oral dose of trazodone and its effect on the activity level of domestic pigeons (Columba livia). We hypothesized that oral administration of trazodone to pigeons would be safe (ie, would not induce any adverse effects) and have no effect on the activity level of treated birds. We also hypothesized that a higher dose of trazodone than that commonly administered to mammals would be required to achieve similar blood drug concentrations and that the terminal half-life of trazodone in pigeons would be shorter than in mammals.

Materials and Methods

Animals

All study procedures were reviewed and approved by the Faculté de Médecine Vétérinaire Animal Care and Use Committee, which operated under the auspices of the Canadian Council on Animal Care. Six adult male domestic pigeons with mean ± SD body weight of 686 ± 95 g were used for the study. All birds were considered healthy on the basis of results of a physical examination, CBC, and fecal examination. Birds were allowed to acclimatize to the research environment for 1 week before initiation of each experiment. For experiments associated with determining the appropriate dose of trazodone and its pharmacokinetics, birds were individually housed in cages with custom-made transparent doors that allowed the birds to be video recorded so behavior could be remotely assessed and not influenced by the presence of human observers in the room. For the accelerometric experiments and the periods between phases, the birds were housed as a group in a large aviary. Throughout the duration of the study, birds were exposed to a natural light cycle and were fed a commercial bird food that consisted of pellets and seeds with ad libitum access to tap water. The weight and fecal output of each bird were monitored on a daily basis throughout the study except on the 3 days when baseline activity data were recorded and handling was prohibited.

Study design

The study consisted of 3 experiments. The initial (pilot) experiment consisted of 2 phases during which the trazodone dose for subsequent experiments was selected on the basis of apparent safety, behavioral effects, and ability to achieve a plasma drug concentration considered therapeutic in other species. During the second experiment, the pharmacokinetics of trazodone following administration of a single dose (30 mg/kg, PO) of the drug to domestic pigeons was determined. The third (accelerometric) experiment consisted of 2 phases during which it was determined whether trazodone could be administered to group-housed pigeons without causing aggression or other behavioral issues and whether the drug affected the activity level of treated birds.

Pilot experiment

The pilot experiment consisted of 2 phases. The study population was divided in half, so only 3 birds were evaluated during each phase. Birds were individually housed in cages for 1 week before (acclimation period) and for 24 hours after trazodone administration. Each cage was equipped with a transparent door. A high-definition digital cameraa was mounted outside the cage in front of the door and used to record video of the bird, which was wirelessly transmitted to a computer in another room where it could be monitored in real time and stored for analysis.

During phase 1, a 2% trazodone hydrochloride aqueous solutionb was orally administered at increasing doses from 3 to 30 mg/kg (ie, 3, 5, 7, 10, 20, 25, and 30 mg/kg) to 3 birds. Each dose was first administered to 1 bird. In the absence of any adverse effect, the same dose was then administered to 2 other birds on subsequent days. For each pigeon, there was a 1-week washout period between doses. The drug was administered by gavage directly into the crop to ensure that each bird received the allotted dose. Birds were remotely monitored for 12 hours after trazodone administration for adverse effects and to assess their activity and attitude. For each bird, partial ethograms were created as described24 by an experienced observer (MRD) for the 3 days before (baseline) and day of trazodone administration. That observer was unware of (blinded to) the treatment administered.

During phase 2, each of 3 birds received 30 mg of trazodone/kg, PO, and was monitored as described for phase 1. From each bird, a blood sample (0.5 mL) was collected by venipuncture of an ulnar or medial metatarsal vein immediately before (0 minutes) and at 15 and 30 minutes and 1, 2, 4, 8, 12, 18, and 24 hours after trazodone administration. Blood samples were placed in blood collection tubes that contained heparin as an anticoagulant and stored in cryotubes at −80°C until processed. The PCV was determined by the microhematocrit method for blood samples collected at 0 minutes and 24 hours after trazodone administration. Then, all blood samples were centrifugedc at 11,200 × g for 30 seconds. Plasma was harvested from each sample, placed in a cryotube, and stored frozen at −80°C until analysis.

Quantification of plasma trazodone concentration—The trazodone concentration in each plasma sample was quantified by HPLC-MS-MS. Protein precipitation was used to extract trazodone from each plasma sample. Briefly, 50 μL of each sample was mixed with 200 μL of an internal standard solution (trazodone-d6 in acetonitrile; concentration, 1 μg/mL) in a 1.5-mL centrifuge tube. The mixture was vortexed vigorously, allowed to set at room temperature (approx 22°C) for 10 minutes, then centrifuged at 12,000 × g for 10 minutes. One hundred fifty microliters of the resulting supernatant was transferred to an injection vial, and chromatographic separation was performed by use of a gradient elution on an analytic columnd (50 × 1.0 mm; internal diameter, 3 μm) thermostated at 30°C. The mobile phase consisted of acetonitrile, water, and formic acid at a ratio of 5:95:0.1, which was injected at a flow rate of 75 μL/min. Following injection, the 5:95:0.1 composition was maintained for 1 minute, switched to a composition with a ratio 80:20:0.1 and maintained for 3 minutes, and then returned to the original conditions. The column was equilibrated for 4 minutes, resulting in a total run time of 8 minutes.

Trazodone quantification was performed by a system that consisted of a linear ion trap mass spectrometere interfaced with a high-performance liquid chromatography unitf that used a pneumatic electrospray ion source. The sheath gas setting was 15 AU, and the electrospray ion source electrode was set at 4,000 V. Mass spectrometry detection was performed in positive-ion mode. Trazodone and trazodone-d6 were analyzed with full-scan tandem mass spectrometry, and quantification of each was based on specific postprocessing selected reaction monitoring of extracted ion chromatograms. The selected reaction monitoring transitions were m/z, 372 → 176 for trazodone and m/z, 378 → 182 for trazodone-d6. The capillary temperature was 300°C, and the capillary voltage was 22 V. The normalized collision energy was 35 V. The analytical range was from 0.05 to 10 μg/mL, and quantification was calculated on the basis of the trazodone-to-trazodone-d6 peak area ratio.

Pharmacokinetics experiment

The pharmacokinetics experiment was conducted 6 weeks after the pilot experiment. During the pilot experiment, oral administration of trazodone to pigeons at a dose of 30 mg/kg was not associated with any adverse effects and resulted in plasma drug concentrations that were similar to those that are considered therapeutic in other species. Therefore, on the basis of those results and allometric scaling calculations, the trazodone dose selected for the pharmacokinetics experiment was 30 mg/kg, PO. Three additional pigeons were used for the pharmacokinetic experiment; trazodone administration, blood sample collection and processing, and determination of plasma trazodone concentration were as described for the pilot experiment.

Pharmacokinetic parameters were calculated by use of a noncompartmental method25 with a pharmacokinetic-pharmacodynamic add-in programg for a commercial spreadsheet program.h For each bird, plasma trazodone concentration-versus-time data were plotted by use of semilogarithmic graphs.

Accelerometric experiment

The accelerometric experiment was conducted 2 months after the pharmacokinetic experiment. All 6 birds were housed as a group in a large aviary during the intervening period and for the duration of the accelerometric experiment. The accelerometric experiment consisted of 2 phases. One week prior to initiation of phase 1, each bird was equipped with and allowed to acclimate to a harness made from self-adherent bandage materiali that contained an ultra-lightweight accelerometer.j The accelerometer was 24 mm in diameter, weighed approximately 7.5 g (approx 1% of the mean body weight of the pigeons), and was positioned on the back of the bird. Activity counts, in the form of digitalized electric impulses, were expressed in AU. Following the 7-day acclimation period, the pigeons were not handled for a period of 3 days so that baseline activity counts could be recorded. Accelerometer data were collected continuously throughout the experiment. Data were then divided into 2-minute epochs and processed by commercial softwarek to derive activity counts for analysis purposes.

Phase 1 of the accelerometric experiment was conducted to assess whether trazodone could be safely administered to group-housed birds without resulting in aggression or other behavioral issues. All 6 pigeons received trazodone (30 mg/kg, PO) by means of gavage directly into the crop, twice, with a 48-hour interval between doses. After a washout period of 8 days, all 6 birds received a volume of water (control) equal to the volume of trazodone administered before the washout period by means of gavage, twice, with a 48-hour interval between doses. Because it was unknown whether trazodone would affect bird activity, all birds received the same treatment at the same time (ie, treatment order was not randomized for individual birds) to minimize the risk of aggression from water-treated birds toward potentially sedated trazodone-treated birds.

Phase 2 was conducted 7 days after completion of phase 1. The protocol for phase 2 was the same as that for phase 1 except that the order in which the treatments (trazodone and water) were administered was randomized by means of a computerized random letter generator for each bird. Treatment randomization was deemed acceptable for phase 2 because no behavioral issues or changes in activity following trazodone administration were observed among birds during phase 1.

Statistical analysis

The performance (accuracy, precision, and limits of quantification) of the HPLC-MS-MS system used to quantify plasma trazodone concentration was assessed by use of information gathered during the pilot and pharmacokinetic experiments. Descriptive data were generated for the pharmacokinetic parameters calculated during both the pilot and the pharmacokinetic experiment. For both phases of the accelerometric experiment, activity count data for each bird were collated for 2 and 15 hours immediately after administration of each dose of trazodone or water; those 2 periods were purposely selected to encompass the expected peak plasma trazodone concentration and duration for which plasma trazodone concentrations were expected to be within the therapeutic range for humans (0.13 to 2.2 μg/mL), respectively. Those activity counts were compared with baseline activity counts that corresponded to the same time of day by means of a repeated-measures linear model that included treatment (1 or 2) as a within-subject factor to account for unequal variances among treatments. The Tukey adjustment was used to control for type I error inflation when post hoc pairwise comparisons were necessary. Results were reported as the mean ± SD, and values of P < 0.05 were considered significant. All statistical analyses were performed with commercial software.l

Results

Pigeons

All 6 pigeons remained healthy and active throughout all 3 experiments of the study. Likewise, fecal output remained consistent and was considered normal throughout the study. The mean ± SD body weight of the birds remained stable (from 686 ± 95 g at the beginning of the study to 714 ± 115 g at the completion of the study).

Pilot experiment

No changes from baseline were detected in the partial ethograms for the pigeons administered trazodone at increasing doses from 3 to 30 mg/kg, PO, during phase 1 of the pilot experiment. The proportion of time birds spent exploring and resting was similar before and after trazodone administration. For the 3 birds of phase 2, the mean PCV at 24 hours after trazodone administration did not differ significantly from that prior to trazodone administration, despite the fact that nine 0.5-mL blood samples were collected during the intervening period. Thus, we concluded that the protocol for blood sample collection would not adversely affect the birds.

Performance of the HPLC-MS-MS

The linearity of the method was assessed by use of blank domestic pigeon plasma that was spiked with a trazodone standard at concentrations ranging from 0.05 to 10.0 μg/mL and a constant concentration (1.0 μg/mL) of trazodone-d6 (internal standard). The trazodone-to-trazodone-d6 peak area ratio was calculated. Each calibration curve consisted of a double blank (plasma sample without analyte [trazodone] and without the internal standard), a zero standard (plasma sample without analyte but with internal standard), and 6 calibration points. Linear regression (weighted, 1/concentration) provided the best fit between the trazodone concentration measured by the instrument and the known trazodone concentration. The calculated correlation coefficients (r) were ≥ 0.9956 for measurement of the trazodone concentration in the plasma of domestic pigeons within an analytic range from 0.05 to 10.0 μg/mL (Figure 1). For best assay performance, it is important that the sample preparation protocol provide a clean extract in a consistent, precise, and reproducible manner at analyte concentrations throughout the analytic range. Different precipitating solvents (acetonitrile, acetone, and methanol) were assessed, and acetonitrile provided the best results in regard to suitable precision and accuracy (within 15%) at the lower limit of quantification and without significant interferences. When acetonitrile was used as the precipitating solvent, the lower limit of quantification for the assay was 0.05 μg/mL, precision (relative SD) was 5.2%, and accuracy (relative error) was 0.6%. The reproducibility of the method was measured by analysis of 6 replicates at each of 3 trazodone concentrations (0.10, 1.0, and 10.0 μg/mL) in domestic pigeon plasma within an analytic run and among 3 individual runs. The calculated precision ranged from 0.4% to 10.3%, and accuracy ranged from −11.1% to 6.5%. The mean intrarun and interrun precision and accuracy for each of the 3 standard concentrations of trazodone were summarized (Table 1), and all were within generally accepted criteria.26

Figure 1—
Figure 1—

Calibration curve for quantification of trazodone in the plasma of domestic pigeons (Columba livia) by HPLC-MS-MS. Blank domestic pigeon plasma was spiked with a trazodone standard at concentrations ranging from 0.05 to 10.0 μg/mL and a constant concentration (1.0 μg/mL) of trazodone-d6 (internal standard). The trazodone-to-trazo-done-d6 peak area ratio was calculated. Each calibration curve consisted of a double blank (plasma sample without analyte [trazodone] and without the internal standard), a zero standard (plasma sample without analyte but with internal standard) and 6 calibration points. Linear regression (weighted, 1/concentration) provided the best fit between the trazodone concentration measured by the instrument and the known trazodone concentration.

Citation: American Journal of Veterinary Research 80, 1; 10.2460/ajvr.80.1.102

Table 1—

Summary statistics for intrarun and interrun precision and accuracy of the HPLC-MS-MS system used to quantify the plasma trazodone concentration for 6 healthy adult male domestic pigeons (Columba livia) that received a single dose (30 mg/kg, PO) of the drug.

 InterrunIntrarun
Known trazodone concentration (μg/mL)Measured concentration (μg/mL)Precision (%)Accuracy (%)Measured concentration (μg/mL)Precision (%)Accuracy (%)
0.100.107 ± 0.01110.36.50.106 ± 0.0098.65.6
1.000.889 ± 0.0141.5 0.913 ± 0.0293.2−8.7
10.009.73 ± 0.040.4−2.79.72 ± 0.040.4−2.9

Values represent mean ± SD measured trazodone concentration, mean relative SD (precision), or mean relative error (accuracy). Reproducibility of the method was measured by analysis of 6 replicates at each of 3 known trazodone concentrations (0.10, 1.0, and 10.0 μg/mL) in blank domestic pigeon plasma within an analytic run and among 3 individual runs.

Pharmacokinetic analysis

The mean ± SD plasma trazodone concentration over time following administration of a single dose (30 mg/kg, PO) of the drug to the 6 study birds was plotted (Figure 2), and the calculated pharmacokinetic parameters were summarized (Table 2). The Cmax and tmax could not be calculated owing to the unexpected rapid absorption of trazodone within the first 30 minutes after administration.

Figure 2—
Figure 2—

Mean ± SD plasma trazodone concentration over time following oral administration of a single dose (30 mg/kg) of the drug to 6 healthy adult male domestic pigeons. The shaded area represents the plasma trazodone concentration range (0.13 to 2.2 μg/mL) that is considered therapeutic for humans. The dashed line represents the line of best fit for the data. The dotted line represents the point at which the line of best fit for the data decreased to below the lower limit of the therapeutic trazodone concentration range for humans.

Citation: American Journal of Veterinary Research 80, 1; 10.2460/ajvr.80.1.102

Table 2—

Mean ± SD values for pharmacokinetic parameters derived for trazodone following oral administration of a single dose (30 mg/kg) of the drug to 6 healthy adult male domestic pigeons.

ParameterMean ± SD
AUC0–24 (μg·h/mL)23.96 ± 6.92
AUC0-∞ (μg·h/mL)24.78 ± 7.89
λ (1/h)0.14 ± 0.05
t½5.59 ± 1.75
Cl/F (L·h/kg)1.31 ± 0.39
Vz/F (L/kg)9.90 ± 2.11

Pharmacokinetic parameters were calculated by noncompartmental analysis. AUC0–24 = Area under the concentration-time curve from time 0 to 24 hours after drug administration. AUC0-∞ = Area under the concentration-time curve from time 0 to infinity. Cl/F = Apparent relative total drug clearance from plasma after oral administration. λz = Terminal rate constant. Vz/F = Apparent relative volume of drug distribution in plasma after oral administration.

Accelerometric experiment

No aggressive behavior was observed when all 6 birds were administered trazodone at the same time during phase 1. Therefore, accelerometric data for phases 1 and 2 were combined for analysis. Consequently, for each bird and treatment (trazodone or water), the activity count during each posttreatment interval evaluated (2 and 15 hours after administration) represented the mean for 4 treatments (ie, both treatments were administered twice during both phases 1 and 2).

The mean activity count was significantly associated with treatment during the first 2 (P = 0.01) and 15 (P = 0.006) hours after administration. During both posttreatment intervals, the mean activity count for birds following water (control) administration was significantly lower than the mean baseline activity count, whereas the mean activity count for birds following trazodone administration did not differ from that at baseline or after water administration (Figure 3).

Figure 3—
Figure 3—

Mean ± SD activity count for 6 healthy adult male domestic pigeons before (baseline; white bars) and during the first 2 and 15 hours after oral administration of trazodone (30 mg/kg; black bars) or an equal volume of water (gray bars) twice at 48-hour intervals during both phases 1 and 2 of the accelerometry experiment. Each bird was instrumented with an ultralightweight accelerometer throughout the experiment, and activity was assessed in 2-minute epochs. Baseline data were acquired over a period of 3 days prior to initiation of phase 1 during which the birds were not handled. The baseline activity count represents the mean activity count for birds over the same hours during each day of the baseline period as those for which the activity counts were recorded after the respective treatments.a,b Within each posttreatment interval, means denoted with different lowercase letters differ significantly (P < 0.05).

Citation: American Journal of Veterinary Research 80, 1; 10.2460/ajvr.80.1.102

For 1 of the 6 pigeons, the mean ± SD activity count during the first 2 hours after trazodone administration (427 ± 45 AU) was approximately twice that at baseline (220 ± 57 AU) and during the first 2 hours after water administration (180 ± 31 AU). However, the mean ± SD activity count during the first 15 hours after trazodone administration for that bird (262 ± 50 AU) did not differ significantly from that at baseline and during the first 15 hours after water administration (154 ± 79 AU). Interestingly, the plasma trazodone concentrations over time for that bird were not higher than those of the other birds.

Discussion

For the 6 healthy adult male domestic pigeons of the present study, a single dose of trazodone (30 mg/kg, PO) resulted in plasma drug concentrations that were similar to those considered therapeutic in other species within 5 minutes after administration. By 1 hour after administration, the plasma trazodone concentration for all 6 pigeons exceeded the therapeutic range for humans and was similar to the Cmax achieved in dogs after administration of the drug at a dose of 50 mg/kg, PO.27,28 In 1 study,14 the mean ± SD tmax was 445 ± 271 minutes for dogs after administtration of trazodone at a dose of 8 mg/kg, PO. The Cmax and tmax of trazodone could not be calculated for the pigeons of this study owing to the unexpected rapid absorption of the drug.

The bioavailability of trazodone was not evaluated for the pigeons of this study because we were concerned about unacceptable adverse effects following IV administration of the drug. In dogs and horses, adverse effects associated with IV administration of trazodone include ataxia progressing to sternal recumbency, tachycardia, signs of nausea, and aggression,14,15 and we believed that adverse effects such as those might be life-threatening for small birds. The mean ± SD estimated bioavailability of trazodone was 84.6 ± 13.2% for dogs of 1 study.14 In humans, the estimated bioavailability ranges from 65% to 80%.28,29

In humans, absorption of trazodone varies unpredictably in fasted individuals; therefore, it is recommended that the drug be administered with food.29 In the present study, the feeding behavior of individual birds prior to trazodone administration was not recorded. The birds had ad libitum access to a commercial ration to mimic the usual feeding conditions for granivorous birds. Review of the videos recorded of the birds revealed that all birds were eating within 1 hour after trazodone administration. Regardless, data suggested that the 2% (20 mg/mL) trazodone aqueous solution was rapidly absorbed following oral administration to domestic pigeons, and administration of 30 mg of trazodone/kg to pigeons resulted in plasma drug concentrations similar to those that are considered therapeutic for other species within 1 hour.

The pharmacokinetic parameters of trazodone did not vary substantially among the pigeons of the present study, unlike the pharmacokinetic parameters of amitriptyline3 and paroxetine4 in parrots, and to a lesser extent, the pharmacokinetic parameters of trazodone in dogs.14 The mean ± SD t1/2 of trazodone for the pigeons of this study (335 ± 105 minutes [5.59 ± 1.75 hours]) was approximately twice that of trazodone for dogs following administration of the drug as a dose of 8 mg/kg, PO (166 ± 47 minutes).14 Prior to study initiation, we suspected that the t1/2 of trazodone would be much shorter in pigeons than in dogs because small species tend to have a higher metabolism and drug elimination is generally positively correlated with blood flow rate.25 In mammalian species, trazodone is primarily metabolized by the liver, and although liver weight and hepatic blood flow are allometrically scalable, hepatic metabolism, including cytochrome P450 isoenzyme (an enzyme responsible for trazodone metabolism) expression, varies widely among species and can affect drug clearance and t1/2.30,31 The expression and function of cytochrome P450 has not been well elucidated in avian species.

In a study28 involving adult men who received between 100 and 200 mg of trazodone, PO, the plasma drug concentration ranged from 0.14 to 2.2 μg/mL. Similar plasma trazodone concentrations are achieved in dogs within 4 to 20 hours after oral administration of the drug at a dose of 8 mg/kg (a dose that generally results in an appropriate clinical response).14,19 For all 6 pigeons of the present study, the plasma trazodone concentration remained > 0.130 μg/mL for 12 hours after drug administration, and the drug was still detectable in the plasma at 24 hours after administration. Further research is warranted to assess the pharmacokinetics of trazodone following administration of multiple doses and to determine the therapeutic plasma trazodone concentration for domestic pigeons.

Trazodone has a very wide margin of safety in mammalian species. The LD50 of trazodone is 610 mg/kg in mice, 486 mg/kg in rats, and 560 mg/kg in rabbits.19,32 In humans, few serious adverse effects are observed when trazodone is administered in the absence of other drugs.11 In dogs, adverse effects associated with trazodone administration include gastrointestinal abnormalities, agitation, sedation, an increase in appetite, perceived behavioral disinhibition, and priapism.16,19 Among 19 cats described in 2 studies,20,21 only 1 became agitated and abnormally vocal following trazodone administration; no other adverse events associated with trazodone administration were described in those 2 studies. Trazodone administration was not associated with sedation or any adverse effects for the pigeons of the present study as determined on the basis of review of behavioral and accelerometric data. During the accelerometric experiment, 1 pigeon had a transient increase in activity relative to that at baseline during the first 2 hours after trazodone administration, which might have been indicative of trazodone-induced agitation similar to that reported in other species. It is unknown whether the absence of sedation following trazodone administration to the pigeons of this study was because the dose administered (30 mg/kg, PO) was insufficient to achieve blood drug concentrations necessary to induce sedation or the mechanism of action of trazodone (eg, affinity for neuroreceptors such as H1 receptors) in birds differs from that in other species. Interindividual variation in the response to psychotropic drugs has been reported in many species, and that variation is not necessarily correlated with plasma drug concentration. For the pigeons of the present study, the mean activity count was significantly decreased from that at baseline after water, but not trazodone, administration. One explanation for that finding is that the decrease in activity caused by handling of the birds for treatment administration was offset by an increase in activity induced by trazodone.

The advent of ultralightweight accelerometers has provided an accurate noninvasive method to monitor the activity of small animals.33 Such accelerometers have proven useful for monitoring the extent of sedation in human patients in intensive care units.34 In the present study, ultralightweight accelerometers were mounted to the pigeons to provide an objective measurement of the extent of activity when birds were housed in a group in a large aviary, where visual evaluation of behavior was challenging. The harnesses used to mount the accelerometers to the study subjects were tolerated well by the birds and allowed them to fly with no apparent difficulty and engage in all normal social behaviors of group-housed birds (vs being isolated in individual cages for ethograms) except bathing, which was restricted because water would have damaged the accelerometers.

The present study had some limitations. The study population was small. Although the pharmacokinetic parameters displayed low interindividual variability and no adverse effects were observed following trazodone administration, individual-specific hypersensitivity to psychotropic drugs has been described in multiple species. Therefore, when psychotropic drug administration is initiated in clinical practice, patients should be started on the lowest dose required to achieve a therapeutic blood drug concentration to mitigate the risk for undesirable effects. Other limitations of this study included the fact that only male domestic pigeons were evaluated and the pharmacokinetics of trazodone were determined following administration of only 1 instead of multiple doses. Sex has a significant effect on the pharmacokinetics of trazodone in other species.8,35 A washout period was not observed during phase 2 of the accelerometric experiment and water or trazodone was administered each day for 4 consecutive days, which may have allowed for some accumulation of the drug. Despite that possibility, no sedative or adverse effects were observed in any of the birds.

Results of the present study suggested that oral administration of a single dose (30 mg/kg) of trazodone to healthy adult male domestic 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. No sedation or adverse effects were associated with that dosage in any of the birds. Ultralightweight accelerometers were successfully used to monitor the activity of study birds when housed as a group in a large aviary and might be beneficial for monitoring the activity of birds in other studies. Further research is necessary to determine the therapeutic concentration of trazodone in domestic pigeons and assess its clinical efficacy for the treatment of anxiety disorders or alleviation of stress.

Acknowledgments

Supported by the Fonds du Centenaire of the Faculté de médecine vétérinaire and the Granby Zoo. The HPLC-MS-MS analyses were performed on instruments funded by the National Sciences and Engineering Research Council of Canada (F. Beaudry Research Tools and Instruments Grants No. 439748-2013).

The authors thank Colombe Otis and Eric Troncy for guidance regarding the accelerometers; Guy Beauchamp for statistical assistance; and Émilie Couture, Jessica Aymen, Rock Boily, and Elizabeth Blair for technical assistance.

ABBREVIATIONS

AU

Arbitrary units

Cmax

Maximum plasma drug concentration

HPLC-MS-MS

High-performance liquid chromatography–tandem mass spectrometry

t1/2

Terminal half-life

tmax

Time to maximum plasma drug concentration

Footnotes

a.

GoPro Hero 4 Silver, GoPro, San Mateo, Calif.

b.

Trazodone, Teva Canada Ltd, Toronto, ON, Canada.

c.

StatSpin MP, Iris Sample Processing, Westwood, Mass.

d.

Phenyl-Gold analytic column, Themo Fisher Scientific, Waltham, Mass.

e.

LTQ XL linear ion trap mass spectrometer, Thermo Fisher Scientific, Waltham, Mass.

f.

Acella HPLC system, Thermo Fisher Scientific, Waltham, Mass.

g.

Zhang Y, Huo M, Zhou J, et al. PK Solver: an add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Programs Biomed 2010;99:306–314.

h.

Excel, Microsoft Corp, Redmond, Wash.

i.

Vetrap, Cardinal Health Canada, Anjou, QC, Canada.

j.

Actiwatch Mini, CamNtech Ltd, Papworth Everard, England.

k.

Actiwatch Activity and Sleep Analysis 7, version 7.38, CamNtech Ltd, Papworth Everard, England.

l.

SAS, version 9.3, SAS Institute Inc, Cary, NC.

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Contributor Notes

Address correspondence to Dr. Desmarchelier (marion.desmarchelier@umontreal.ca).