Trazodone CYP3A4/5/7 substrate

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. 

Nefazodone is a phenylpiperazine structurally related to trazodone. Both nefazodone and trazodone block the reuptake of serotonin at presynaptic neurones and block aj-adrenoceptors, but have no apparent effect on dopamine. Unlike trazodone, nefazodone blocks the reuptake of noradrenaline. Compared to the tricyclics, neither drug has very significant antimuscarinic effects, but trazodone also has marked sedative properties. Nefazodone is an inhibitor of the cytochrome P450 isoenzyme CYP3A4 and therefore it will inhibit the metabolism of drugs by this route. For a list of CYP3A4 substrates see Table 1.4 , (p.6). Note that, nefazodone has largely been withdrawn due to adverse hepatic effects. 

Trazodone is a substrate but not a potent inhibitor of CYP3A4. As a result, combining trazodone with potent inhibitors of CYP3A4, such as ritonavir or ketoconazole, may lead to substantial increases in trazodone levels. 

The possibility of drug-drug interactions with trazodone and other substrates, inducers, and/or inhibitors of CYP3A4 exists (75). 

It appears that the plasma levels of trazodone may be increased by fluoxetine due to inhibition of cytochrome P450 isoenzymes by fluoxetine and/or norfluoxetine. Trazodone is a substrate for CYP3A4 and, although fluoxetine is a weak inhibitor, its metabolite norfluoxetine is a moderate inhibitor of this enzyme. vitro data suggest citalopram has little inhib-... 

An in vitro study demonstrated that ketoconazole inhibited the metabolism of trazodone to its prineipal metabolite, meta-chlorophenylpipera-zine. Trazodone is a substrate for the eytochrome P450 isoenzyme CYP3A4 and inhibitors of this enzyme sueh as ketoconazole or itraconazole may inhibit its metabolism, leading to substantial inereases in trazodone plasma concentrations with the potential for adverse effects. " The FDA in the US and the manufacturers of trazodone recommend that a lower dose of trazodone should be considered if it is given with a potent CYP3A4 inhibitor such as ketoconazole or itraconazole. " However, the UK manufacturer also suggests that the combination should be avoided where possible. ... 

Trazodone is a substrate for CYP3A4 and inhibitors of this enzyme such as ritonavir and indinavir may inhibit its metabolism, leading to substantial increases in trazodone plasma concentrations with the potential for adverse effects. ... 

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