Pharmacology & Toxicology 1992, 71, 150-153.

Single Dose Pharmacokheticsof Trazodone in Healthy Subjects -

Odd G. Nilsen and Ola Dale University of Trondheim, Department of Pharmacology and Toxicology, Faculty of Medicine, Center for Medical Technics, N-7005 Trondheim, Norway (Received February 4, 1992; Accepted February 17, 1992) Abstract: Eight healthy subjects were administered trazodone-HCI orally (100 mg) with and without food and by infusion in a three way cross-over study. Unchanged trazodone was determined in semm 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 1.88k0.42 to 1.47+0.16 pg/ml, and increased the time for reaching maximum concentration from 1.3k0.8 hr to 2.0k 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 k 4 per cent, respectively. The apparent volume of distribution and total body clearance for trazodone were estimated to 0.84k0.16 I / kg and 5.3k0.9 Vhr, respectively. The terminal elimination half-life of 7.3 k0.8 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.

Trazodone, 2-3-(4-m-chlorophenyl-l-piperazinyl)propyl1,2, 4-triazol-4.3-pyridin-3(2H)-one is a weak, but specific inhibitor of synaptosomal uptake of serotonin (Brogden et al. 1981). It is an antidepressant drug which has proved effective in several mental disorders including anxiety and endogenous depression (Brogden et al. 1981; Coccaro & Siever 1985). Although trazodone was introduced into clinical practice in 1982 (Coccaro & Siever 1985), relatively few reports on basic pharmacokinetic parameters have been published. The aim of this study was t o evaluate basic pharmacokinetic parameters, bioavailability and interindividual variability for trazodone in eight healthy subjects after intravenous, oral fasted and oral non-fasted administrations. Trazodone concentrations in serum and urine were determined by a high performance liquid chromatographic technique (HPLC). Materials and Methods Eight healthy volunteers, four males and four females, with normal clinical chemical values from blood, serum and urine analyses, participated in the study. Their age and body weight ranged from 25 to 34 years and 50 to 79 kg, respectively. They were all free from other drugs. Informed concent was given according to the Helsinki declaration, and the study was approved by the Hospital Ethics Committee, and the Medicines Control Authority, Oslo, Norway. During the study arterial blood pressure (non-invasive) and radial pulse rate were recorded and the volunteers observed for adverse reactions. The study was a three way cross-over design with wash-out periods of one week between treatments.Trazodone hydrochloride capsules (Molipaxin, 100 mg, Roussel Laboratories Ltd., London, U.K., Lot. 09139F9) were administered orally after overnight fasting (food intake was allowed 3 hr after administration) and after a standardized breakfast. Intravenous infusion of 90 mg trazodone hydrochloride (5.88 mg/ml in 0.9% sodium chloride containing 410

mg sorbitol, Angelini, Roma LOT 114711) was performed by an electric pump (Injectomat 50 from DIACOR A/S) at a constant infusion rate of 1.7 mllmin. for 9 min. The volunteers were allowed to eat a standardized breakfast before start of infusion. Blood samples (6 to 8 ml) were drawn through a venflon cannula in an arm vein and were allowed to clot for 45 min. at room temperature. Serum was obtained by centrifugation for 10 min. at 1100 x g. Blood collection was performed before and at 15 min., 30 min., 45 rnin., 1 hr, 1.25, 1.5, 1.75, 2.0, 2.5, 3.0, 4.0, 5.0,6.0, 8.0, 10.0, 12.0,24.0 and 26 hr after oral drug intake. The blood sampling intervals were identical after intravenous infusion with exception of the 1.75 hr sample which was replaced by a 10 min. sample. Urine was collected in the following intervals: -2 to 0, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 10, 10 to 12, 12 to 14, 14 to 24 and 24 to 26 hr. Trazodone was stable in frozen serum and urine at - 20" for more than eight weeks. Unchanged trazodone in serum and urine was determined by high performance liquid chromatography (Varian model 5000, UV detector) after a basic extraction (pH 12.8) of 1 ml of serum or urine into 5 ml diethyl ether. After evaporation at room temperature with N,, the residue was dissolved in 0.25 ml 0.01 N H,S04. A Spherisorb 5 S ODS reverse phase column (5 pm x 25 cm) and a mobile phase of acetonitrile: 0.1 N HISO,= 18:l were used. The flow rate was 2.0 ml/min. and trazodone was detected at 254 nm. 2-3-(4-m-chlorophenyI- 1 -piperazinyl)-propyl-5-methyl-4-phenyl-triazol-3-(2H)-one was used as internal standard. The retention times for the internal standard and trazodone were 9.6 and 11.4 min., respectively. Linearity of unchanged trazodone in serum of urine was demonstrated from 0.025 to 20 pg/ml. The detection limit of trazodone was 0.025 pg/ml. Trazodone recovery was close to 100% and the day to day coefficient of variation (n=4) was 10 and 4% at concentrations of 0.25 and 2.0 pg/ml, respectively. Model independent pharmacokinetic parameters were calculated. The elimination rate constant k, was determined from the linear part (8 to 26 hr) of the semilogarithmic serum concentration-time plot, computerized as the least square regression line with equal weight on each point. The elimination half-life t,,, was calculated as ln2/k,. The area under the serum concentration-time curve from zero to infinite time AUCo-, was calculated by the trapezoidal rule using each experimental point from 0 to 26 hr with addition of the

151

TRAZODONE PHARMACOKINETICS rest area C,,/k, where C26is the serum concentration of trazodone measured at 26 hr. Bioavailability F was estimated from the ratio between AUCOo-, after oral and intravenous administration. The apparent volume of distribution V, was calculated as D/,4UCo_,. k, where D is the intravenous dose given and AUCo-, the corresponding area under the curve. Total body clearance CI, as D / AUCo_,. T, and C,,, the maximum serum concentration and the time needed to reach the maximum serum concentration, respectively, were taken from experimental values (Gibaldi & Pemer 1975). Statistical significance was determined by the Student’s t-test for paired values and by comparison of two means. P-values less than 0.05 was considered significant.

Results The mean time courses of trazodone in serum after oral or intravenous administrations are shown in fig. 1. After the fasting oral intake, irregularities were observed around maximum serum concentration. These irregularities were observed in all individuals, showing two or three major serum peaks 0.5 to 3 hr after drug intake. Absorption characteristics of trazodone are shown in table 1. Trazodone is absorbed rapidly with small interindividual variations as judged by the C, and T,, values. Food decreased C, by 22%, increased T,, by 51% and increased TI, by 133%, all statistically significant (P

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. Unchange...
330KB Sizes 0 Downloads 0 Views