Cytochrome SSRI metabolism

SSRI = Selective serotonin reuptake inhibitor NSAID = Nonsteroidal anti-inflammatory drug CYP = cytochrome P-450 NAT2 = N-acetyl transferase type 2 J = Japanese C = Chinese A = African American. Poor metabolizers are not always at increased risk of ADR. 

There are a number of other methods mentioned in the literature, some of which (such as the combination of a TCA with an MAOI) are potentially cardiotoxic and not to be recommended. More recently, a combination of an SSRI with a TCA has become popular but is not to be recommended because of the probability of metabolic interactions involving the cytochrome P450 system that can increase the tissue concentration of even a modest dose of a TCA to a cardiotoxic level. 

P450 system Concomitant use of SSRIs with drugs metabolized by cytochrome P4502D6 may require lower doses than usually prescribed for either paroxetine or the other drug because paroxetine may significantly inhibit the activity of this isozyme. 

Selective serotonin reuptake inhibitors. Currently available selective serotonin reuptake inhibitors (SSRIs) include fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram. At present, expert opinion does not support the usefulness of these serotonergic compounds in the treatment of core ADHD symptoms (National Institute of Mental Health, 1996). Nevertheless, because of the high rates of comorbidity in ADHD, these compounds are frequently combined with effective anti-ADHD agents (see Combined Pharmacotherapy, below). Since many psychotropics are metabolized by the cytochrome P450 system (Nemeroff et ah, 1996), which in turn can be inhibited by the SSRIs, caution should be exercised when combining agents, such as the TCAs, with SSRIs. 

All SSRIs (e.g., Feonard et ah, 1997) and in particular fluoxetine, Fluvosamine and paroxetine are metabolized by hepatic cytochrome P450 enzymes. Therefore, it is important to be aware of the possibility that the therapeutic or toxic effects of other medications metabolized by the cytochrome P450 isoenzyme system can be increased. Substantial inhibition of these isoenzymes converts a normal metabolizer into a slow metabolizer with regard to this specific pathway. Inhibition of the hepatic oxidative isoenzymes has been associated with a reduction, to a varying extent, in the clearance of many therapeutic agents, including the TCAs, several neuroleptics, antiarrhythmics, theophy-lene, terfenadine, benzodiazepines, carbamazepine, and warfarin (for a complete list, see Nemeroff et ak, 1996). 

Differences in biotransformation capacities have been identified for at least two distinct groups poor metabolizers and extensive metabolizers. Poor metabolizers demonstrate a deficiency in one or more pathways of the cytochrome P/450 enzyme system. Since the metabolism of antidepressants and neuroleptics depends on this system (see appendix A), poor metabolizers may be at risk for complications of therapy. For certain tricyclic antidepressants and neuroleptics, it has been established that these individuals will demonstrate increased serum levels and exaggerated medication response. Additionally, they wiU be more susceptible to side effects. Although data is limited on the SSRIs, similar patterns are evident. 

SSRIs can inhibit hepatic isoenzymes 2D6 of the cytochrome P450 system (CYP2D6), which is involved in the oxidative metabolism of numerous drugs. 

SSRIs are metabolized by cytochrome p450 enzymes in the liver. Most SSRIs inhibit CYP2D6, fluvoxamine (10) inhibits CYP1A2, and fluoxetine (9) inhibits CYP3A4. Consequently, these drugs may interfere with the metabolism of a number of other agents. 

Oxidative metabolism of clozapine was found to correlate with caffeine metabolism (462)and is thus largely carried out by cytochrome P4501A2 (CYP1A2). No correlation with CYP2D6 polymorphism was found (461, 462). Several interaction studies of clozapine with SSRI antidepressants have been reported (465-469). Fluvoxamine increased plasma concentrations of clozapine in schizophrenic patients (463,464), presumably through inhibition of CYP1A2 catalyzed N-demethylation (465). Fluoxetine was found to increase the plasma concentrations of clozapine and its major metabolites, suggesting that this SSRI must interfere with pathways other than N-demethylation and N-dealkylation (466). Two other SSRIs, paroxetine (463) and citalopram (467), had no apparent effects on clozapine levels. 

SSRI drug interactions The SSRls are inhibitors of hepatic cytochrome P450 isozymes, an action that has led to increased activity of other drugs including tricyclic antidepressants and warfarin. Huvoxamine inhibits the metabolism of cisapride, astemizole, and terfena-dine, and the resultant cardiotoxicity has led to the withdrawal of the latter two thugs (see Table 30-3). Citalopram causes fewer drug interactions than other SSRls. 

In a study in healthy subjects fluoxetine 20 mg daily for 10 days decreased the oral clearance of a single 400-mg dose of propafenone by 34% for both the R- and 5-enantiomers. The peak plasma levels increased by 39% for 5-propafenone and by 71% forR-propafenone. However, there were no differences in the changes to the PR and QRS intervals. Fluoxetine is an inhibitor of the cytochrome P450 isoenzyme C YP2D6, which is responsible for the metabolism of propafenone to its primary active metabolite 5-hydroxypropafenone (for more detail see mechanism under Propafenone -i- Quinidine , above). In vitro data have shown that, of the SSRIs, fluoxetine is the most potent inhibitor of propafenone 5-hydroxylation, and that paroxetine would also be expected to interact. As with... 

Movement disorders and raised antipsychotic serum levels seem most common with fluoxetine and paroxetine, possibly because they inhibit the metabolism of some antipsychotics by the cytochrome P450 isoenzyme CYP2D6. However, the movement disorders may just be a result of the additive adverse effects of antipsychotics and SSRIs. Fluoxetine alone has been shown to occasionally cause movement disorders. "... 

Fluvoxamine inhibits the cytochrome P450 isoenzyme CYP1A2, which is the major isoenzyme involved in the metabolism of olanzapine, resulting in increased olanzapine levels and adverse effects. All SSRIs affect CYP2D6 (to differing extents). This isoenzyme has a minor role in olanzapine metabolism, and therefore SSRIs other than fluvoxamine have only a small effect on olanzapine levels. 

The reason for the rise in perhexiline levels is not known, but it seems likely that these SSRIs can inhibit its metabolism, probably via the cytochrome P450 isoenzyme CYP2D6. The general importance of these interactions is also not known, but it would now be prudent to monitor the outcome of concurrent use for perhexiline toxicity and consider monitoring perhexiline serum levels where possible. The perhexiline dosage may need to be reduced. More study is needed. 

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