Trazodone metabolism

Yasui N, Otani K, Kaneko S, Ohkubo T, Osanai T, Ishida Mihara K, Kondo T, Sugawara K, Fukushima Y. Inhibiticn of trazodone metabolism by thioridazine in humans. Ther Drug Momt( 99S) 17,333-5. 

Rotzinger, S, Bourin, M, Akimoto, Y, Coutts, RT and Baker, GB (1999) Metabolism of some second and fourth generation antidepressants iprindole, viloxazine, buproprion, mianserin, maprotiline, trazodone, nefazodone and venlafaxine. Cell. Molec. Neurobiol. 19 427 42. 

Rotzinger S, Fang J, Baker GB. 1998. Trazodone is metabolized to m-chlorophenylpiperazine by CYP3A4 from human sources. Drug Metab Dispos 26 572. 

Metabolism/Excretion-Trazodone is extensively metabolized in the liver and is a CYP3A4 substrate. Elimination is biphasic, with a half-life of 3 to 6 hours and 5 to 9 hours, respectively, and is unaffected by food. 

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). 

Trazodone has relatively few drug interactions. Medications that induce or inhibit first-pass metabolism may affect trazodone s plasma concentration. Even though trazodone is commonly used for SSRI-induced insomnia, it may be counter productive. Compounds such as... 

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... 

Baxter LR, Phelps ME, Mazziotti JC, et al Cerebral metabohc rates for glucose in mood disorders. Arch Gen Psychiatry 42 441-447, 1985 Baxter LR Jr, Thompson JM, Schwartz JM, et al. Trazodone treatment response in obsessive-compulsive disorder—correlated with shifts in glucose metabolism in the caudate nuclei. Psychopathology 20 (suppl 1 114-122, 1987 Beale MD, Kellner CH, Pritchett JT, et al Stimulus dose-titration in ECT a 2-year clinical experience. Convulsive Therapy 10 171-176, 1994 Beale MD, Kellner CH, Pritchett JT, et al ECT for OCD. J Clin Psychiatry 56 81-82, 1995... 

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. 

Trazodone is rapidly absorbed, with peak plasma concentrations at 0.5-2 hours. It is extensively metabolized and eliminated mainly via the kidneys, with a half-life of 13 hours for total drug and metabolites. 

SSRIs DULOXETINE, ST JOHN S WORT, SSRIs, TCAs, TRAZODONE T risk of serotonin syndrome >- For signs and symptoms of serotonin toxicity, see Clinical Features of Some Adverse Drug Interactions, Serotonin toxicity and serotonin syndrome Additive effect. In addition, TCAs inhibit CYP2D6-mediated metabolism of SSRIs Caution with co-administration with TCAs or trazodone. Specialist advice should be sought and alternatives considered. Avoid co-administration of two SSRIs, and SSRIs with duloxetine or St John s wort... 

IMATINIB 1. ANTIARRHYTHMICS -flecainide, mexiletine, propafenone 2. ANTIDEPRESSANTS - fluoxetine, paroxetine, TCAs, trazodone, venlafaxine 3. ANTIPSYCHOTICS -clozapine, haloperidol, perphenazine, risperidone, thioridazine 4. BETA-BLOCKERS - metoprolol, propanolol, timolol 5. DONEPEZIL 6. METHAMPHETAMINE Imatinib may cause t plasma concentrations of these drugs, with a risk of toxic effects Inhibition of CYP2D6-mediated metabolism of these drugs Watch for early features of toxicity of these drugs... 

Broom 2. Ginkgo biloba 3. Scopolia 4. Yohimbine 1. TCAs (e.g. amitriptyline, nortriptyline, clomipramine) 2. SSRIs (e.g. fluvoxamine fluoxetine, paroxetine) 3. Venlafaxine 4. Trazodone May develop cardiac arrhythmias and side-effects such as dryness of the mouth, retention of urine and tachycardia, t sedation Broom contains cardioactive alkalamines such as sparteine Inhibits metabolizing enzymes Anticholinergic properties (hyoscine present in scopolia may worsen side-effects of TCAs-additive antimuscarinic effects) Yohimbine alone can cause hypertension, but lower doses cause hypertension when combined with TCAs Unknown mechanism (ginkgo t sedative effects of trazodone) St John s wort inhibits the uptake of serotonin and thereby t serotonin levels Avoid concomitant use. An SSRI may be a better alternative to be used with broom... 

CYP1A2 Multiple Phase I metabolic pathways Theophylline Imipramine, desipramine, trazodone, hexobarbital, flurazepam... 

Trazodone Concurrent use may cause serotonin syndrome. SSRIs may inhibit the metabolism of trazadone resulting in increased toxicity. 

Kalgutkar, A.S. et al., Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4, Chem. Biol. Interact., 155(1-2), 10, 2005. 

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