Plasma Trazodone Concentrations Research Articles

Pharmacokinetic, sedative, and physiological effects of oral compounded formulations of trazodone alone or in combination with gabapentin in male cats.

Trazodone and gabapentin are common oral sedatives in cats, used alone or combined, but no pharmacokinetic studies exist for trazodone in this species. The objective of this study was to determine the pharmacokinetics of oral trazodone (T) alone, or in combination with gabapentin (G) in healthy cats. Cats (n = 6) were randomly allocated to receive T (3 mg/kg) intravenously (IV), T (5 mg/kg) orally (PO), or T (5 mg/kg) and G (10 mg/kg) PO with a 1-week washout period between treatments. Heart rate, respiratory rate, indirect blood pressure, and level of sedation were assessed, and venous blood samples were collected serially over 24 h. Analysis of plasma trazodone concentration was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Oral T administration resulted in a bioavailability of 54.9(7-96)%, and 17.2(11-25)% when administered with G. Tmax 0.17 (0.17-0.5) and 0.17 (0.17-0.75) h; Cmax 1.67 ± 0.91 and 1.22 ± 0.54 μg/mL, AUC 5.23 (2.0-18.76) and 2.37 (1.17-7.80) h*μg/mL; T1/2 5.12 ± 2.56 and 4.71 ± 1.07 h; for T and TG, respectively. Sedation was significant when compared to baseline in all groups from 20 or 45 min to 8 h indicating some lag between peak plasma concentration and sedative effects. Physiological variables remained within normal limits. This study concludes that oral trazodone is rapidly absorbed in healthy cats. Addition of gabapentin did not result in more profound sedation, showing no clinical advantage of combining these drugs in this study population.

Investigation of the effects of orally administered trazodone on intraocular pressure, pupil diameter, physical examination variables, and sedation level in healthy equids.

To investigate the effects of orally administered trazodone on intraocular pressure (IOP), pupil diameter measured in the vertical plane (ie, vertical pupil diameter [VPD]), selected physical examination variables, and sedation level in healthy equids. 7 horses and 1 pony. Food was withheld for 12 hours prior to drug administration. After baseline (time 0) sedation scoring, physical examination, and measurement of IOP and VPD, equids received 1 dose (approx 6 mg/kg) of trazodone orally. Examination and measurement procedures were repeated 0.5, 1, 2, 4, 8, 12, and 24 hours after drug administration. Blood samples were collected at each time point for analysis of plasma trazodone concentrations. Repeated-measures analysis was used to compare examination results between downstream time points and baseline. 7 of 8 equids had mild sedation from 0.5 to 8 hours after treatment; compared with baseline values, mean IOP was significantly lower from 0.5 hours to 8 hours, mean VPD was significantly smaller at 0.5 hours, and mean rectal temperature was significantly lower from 1 to 8 hours after drug administration. Adverse effects (signs of excitement in 1 equid and sweating in 4) were self-limiting and considered minor. Mean maximum plasma concentration of trazodone was 1,493 ng/mL 0.75 hours after administration, and terminal half-life of the drug was 9.96 hours. The described oral dose of trazadone elicited sedation with a few self-limiting adverse effects in the study sample. Drug effects on IOP and VPD may alter ocular examination findings. Further investigation is warranted prior to use of trazodone for sedation in equids, particularly those with ophthalmic conditions.

Pharmacokinetics and efficacy of trazodone following rectal administration of a single dose to healthy dogs.

To determine the pharmacokinetics and efficacy of trazodone following rectal administration of a single dose to healthy dogs. 6 healthy adult dogs. Each dog received a single dose of trazodone (approx 8 mg/kg) per rectum. Trazodone tablets were crushed into a powder, mixed with 5 mL of tap water, and injected into the rectum via a red rubber catheter. Sedation scores were assigned, and blood samples were collected for determination of plasma trazodone concentration at predetermined times before and after drug administration. Pharmacokinetic parameters were estimated by noncompartmental analysis. Plasma trazodone concentration remained below the detection limit for 1 dog even though it became moderately sedate. Median (interquartile [25th to 75th percentile] range [IQR]) maximum plasma trazodone concentration and volume of distribution and clearance corrected for bioavailability were 1.00 μg/mL (0.66 to 1.40 μg/mL), 10.3 L/kg (7.37 to 14.4 L/kg), and 639 mL/kg/h (594 to 719 mL/kg/h), respectively. Median time to maximum plasma trazodone concentration and elimination half-life were 15 minutes (range, 15 to 30 minutes) and 12 hours (IQR, 7.99 to 12.7 hours), respectively. All dogs became mildly or moderately sedate, and the extent of sedation was maximal at a median of 30 minutes (IQR, 30 to 60 minutes) after trazodone administration. No adverse effects were observed. Rectal administration of trazodone may be a viable option for sedation and treatment of anxiety in dogs for which administration of sedatives and anxiolytics by other routes is contraindicated. Further research is necessary to better elucidate the pharmacokinetics and efficacy of trazodone following rectal administration and determine optimal dosing.

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

To determine the pharmacokinetics of a single oral dose of trazodone and its effect on the activity of domestic pigeons (Columba livia). 6 healthy adult male domestic pigeons. 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. 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. 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.

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).

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.

Plasma Trazodone Concentrations in Elderly Depressed Inpatients

Twenty-three depressed patients with an average age of 78.86 were treated with trazodone in dosages averaging 354.3 mg/day. Despite pretreatment cardiac conduction delay in 30%, no electrocardiographic abnormalities were produced or exaggerated during the study. Plasma steady state levels averaged 1,474.4 ng/ml and significantly correlated with dosage at r = 0.415. In a subgroup of 13 patients, six who sustained good short-term response to trazodone had lower mean steady state plasma levels than seven who did not, suggesting that plasma levels about 1,500 ng/ml may not be therapeutic in the short run.

Acute Trazodone Poisoning: Clinical Signs and Plasma Concentrations

A total of 70 patients presenting with suspected acute trazodone poisoning were notified to the Poisons Unit (National Poisons Information Service for England) from August 1980 until March 1983. Detailed follow-up information was obtained on 41 patients, 22 of whom were thought to have ingested trazodone alone. In these latter patients drowsiness (11), ataxia (5), nausea/vomiting (4) and dry mouth (2) were the manifestations of toxicity reported most frequently, only 2 patients became unconscious (grade 2 or 3 coma), and all recovered uneventfully with no more than minimal supportive therapy. The presence of trazodone was confirmed in 8 out of 9 patients from whom specimens (blood and urine) were received. The highest plasma trazodone concentrations (15 and 19 mg/l, respectively) were both associated with only drowsiness and ataxia. However, in 2 further patients moderate plasma trazodone concentrations (4.2 and 8.2 mg/l, respectively) were associated with deep (grade 3-4) coma, although 1 of these latter patients had also ingested ethanol (plasma concentration 3.0 g/l). Although acute trazodone poisoning does not appear to be associated with cardiac arrhythmias or convulsions, these results emphasise that drowsiness and ataxia are commonly encountered, while coma may occur in severe cases. The possible contribution of metabolites of trazodone to toxicity and the potentiating effect of co-ingested drugs or alcohol must be remembered.