Trazodone liver

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). 

In a fatality in which a woman was found drowned in a bath following the ingestion of about 2 to 4 g of trazodone, the following postmortem concentrations were reported blood 15pg/ml, bile 45pg/ml, liver 57 pg/g, urine 2.5 pg/ml (D. Demorest, J. analyt. Toxicol., 1983, 7,63). 

Dantrolene, isoniazid, phenytoin, nitrofurantoin, and trazodone have been reported in association with a type of autoimmune-mediated disease in the liver. Patients experience periods of symptomatic hepatitis followed by periods of convalescence, only to repeat the experience months later. It is a progressive disease with a high mortality rate and is more common in females than males. Antinuclear antibodies appear in most patients. These drugs appear to form... 

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. 

Phenytoin, a liver enzyme inducer, decreases serum levels of TCAs (especially desipramine and clomipramine). An increase in serum levels of nortriptyline and trazodone has also been reported. In these cases, the net effect of enzyme induction (by phenytoin) and enzyme inhibition (by TCAs) seem to be in favor of the inhibitory effects. Carbamazepine also induces liver enzymes, with a consequent reduction in serum levels of TCAs (amitriptyline, desipramine, doxepin, and nortriptyline). These effects of carbamazepine have not been observed with clomipramine, but have been reported with selective serotonin reuptake inhibitors (SSRIs). 

Trazodone is extensively metabolized in the liver by N-dealkylation to its primary active metabolite, m-chlorophenylpiperazine (m-CPP), which subsequently undergoes aromatic hydroxylation to p-hydroxy-m-CPP (Fig. 21.23) (75). In vitro studies indicate that CYP3A4 is the major isoform involved in the production of m-CPP from trazodone (and CYP2D6 to a lesser extent). The p-hydroxy-m-CPP and oxotriazolopyridine-propionic acid (the major metabolite exoreted in urine) are conjugated with glucuronic acid. Less than 1 % of a dose is excreted unmetabolized. 

Trazodone is highly metabolized in the liver by hydroxylation, pyridine ring splitting, oxidation, and A -oxidation, with <1% of the unchanged drug appearing in the urine and feces. 

Patients given phenothiazines and trazodone should be monitored for signs of excessive hypotension and should have their liver function tests closely monitored. 

Liver Fulminant hepatic failure has been attributed to a comiDination of venlafaxine and trazodone [61 ]. 

A 48-year-old woman with normal liver function took venlafaxine 75 mg/day and trazodone 200 mg/day for depression and 4 months later developed increasing jaundice and encephalopathy. She had markedly raised transaminases and bilimbin. There were no other explanations for her hepatic failure, and she received an urgent liver transplantation. The pathology showed severe acute hepatitis compatible with toxic acute liver failure. She recovered fully, and had normal liver function tests 1 year later. 

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