Trazodone pharmacokinetics

Trazodone is well absorbed after oral administration. It achieves peak plasma levels 1-2 hours following ingestion. The bioavailability of trazodone is 60%-80% with doses between 100 and 200 mg. Trazodone exhibits nonlinear pharmacokinetics because of saturable first-pass metabolism in the liver. Trazodone is metabolized by CYP450-3A4, and its active metabolite, m-CPP, is metabolized through CYP450-2D6. The half-life of the parent compound is 5 to 9 hours, and the half-life of m-CPP is 4 to 9 hours. It is excreted primarily in the urine (Preskorn, 1993). 

Gender-related effects have been evaluated for trazodone, and clearance is lower for elderly men compared with elderly women [D. J. Greenblatt et al. 1987]. Differences exist in the metabolic rate of the SRI sertraline [Warrington 1991]. The effect of OCs on the pharmacokinetics of SRls or... 

An interaction between G. biloba administered as 80 mg leaf extract twice a day and low-dose trazodone (20 mg twice daily) was suspected in a patient with Alzheimer s disease, who took the two products together. It is postulated that a pharmacodynamic (increased gamma-aminobutyric acid-ergic activity) and pharmacokinetic mechanisms [increased metabolism of trazodone to w-chlorophenylpiperazine (w -CPP), which acts on the benzodiazepine-binding sites and releases gamma-aminobutyric acid] contribute to the observed effect (32). Table 2 provides a list of reported pharmacodynamic and pharmacokinetic interactions involving ginkgo. 

The pharmacokinetics of these drugs are similar to those of the tricyclics (Table 30-2). Some may have active metabolites. Trazodone and venlafaxine have short plasma half-lives, which mandates divided doses during the day when beginning treatment, though once-a-day dosing may be possible later. Extended-release forms of bupropion and venlafaxine allow for once-a-day dosing in some patients from the outset. 

O. G. Nilsen and O. Dale, Single dose pharmacokinetics of trazodone in healthy subjects, Pharmacol. Toxicol., 77 150(1992). 

Several LC-MS and LC-MS/MS methods were developed in plasma for only one antidepressant and, sometimes, its major metabolite(s) to perform pharmacokinetic, bioavailability, or bioequivalence studies. Analytical methods developed for these purposes require very low LLOQ values and, usually, narrow linear ranges covering the low range of the therapeutic concentrations are validated. In this context, several methodologies were described for the determination of fluoxetine [94, 95, 98-100], paroxetine [44, 71, 85, 101, 102], venlafaxine [48, 61, 64, 86, 103,104], sertraline [62, 68, 83], citalopram [46, 89] and escitalopram [105], mianserine [106, 107], mirtazapine [42], trazodone [84], nefazodone [51, 81], duloxetine [47, 50, 73], and bupropion [43], Deuterated analogues of the analyte of interest or of other drugs were employed by few authors as IS [43, 61, 73, 81, 85, 99] however, in most of these methods, another antidepressant or other therapeutic drug was used for this purpose. 

Propotnik M, Waschgler R, Konig P, Moll W, Conca A. Therapeutic drug monitoring of trazodone are there pharmacokinetic interactions involving citalopram and fluoxetine Int J Clin Pharmacol Ther 2004 42 120-4. 

Introduction - Concern over the safety of tricyclic antidepressants (TCA)f> has maintained the Impetus to develop new drugs. Compounds reviewed in 1978 Include mianserin,3. nomlfensin, and all non-TCA. S5rm-posia covered dothlepin, mianserin, nomifensin, and trazodone. The uses of L-tryptophan and 5-hydroxytryptophan (5-HTP) in depression and the properties of the new antidepressants " were summarized. The neuropharmacology of depression, and the mechanism of action and pharmacokinetics of antidepressants were reviewed, and the monoamine theory reassessed.20... 

For MDD with severe anxiety, mirtazapine, TCAs, trazodone, and benzodiazepines should be considered as adjunctive therapy. If the patient is not at least moderately improved after 4-8 weeks, the treatment regimen should be reappraised. Compliance should be checked. It is important to consider pharmacokinetic/pharmacodynamic factors (this may require an evaluation of serum levels of the antidepressant medication), general medical comorbidities, and comorbid psychiatric disorders, including substance abuse and significant psychosocial problems. The initial therapeutic treatment dose should be gradually maximized. For partial responders, the trial should be extended by... 

E. Pharmacokinetics. These drugs have large volumes of distribution (Vd = 12-88 L/kg, except trazodone [Vd = 1.3 L/kg]). Most are eliminated via hepatic metabolism (paroxetine is 65% renal). (See also Table 11-59, p 381.)... 

These cases and studies suggest that the concurrent use of trazodone and fluoxetine can be useful and uneventful but it would seem prudent to monitor the outcome for any evidence of increased adverse effects. Citalopram would not be expected to have a pharmacokinetic interaction. However, the cases with fluoxetine suggest that a pharmacodynamic interaction may be possible, and therefore a degree of caution would be prudent if trazodone is given with any SSRI. 

Maes M, Westenberg H, Vandoolaeghe E, Demedts P, Wauters A, Neels H, Meltzer HY. Effects of trazodone and ftuoxetine in the treatment of major depression therapeutic pharmacokinetic and pharmacodynamic interactions throu formation of meta-chlorophenylpiperazine. JCftnP c <>pftamiaco/(1997) 17,358-64. 

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