Fluoxetine cytochrome P450 inhibition

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). 

Aripiprazole is hepatically metabolized, mainly by two cytochrome P450 enzymes CYP 2D6 and CYP 3A4. Therefore, dosage adjustments are necessary when this medication is given with other medications that either inhibit or induce these enzymes. For example, the dose of aripiprazole should be halved when this medication is given with ketoconazole, a CYP 3A4 inhibitor, or at least decreased when given with fluoxetine, a CYP 2D6 inhibitor. When aripiprazole is given with CYP 3A4 inducers such as carbamazepine, the dose should be doubled. 

Drugs that may inhibit cytochrome P450 metabolism of other drugs include amiodarone, androgens, atazanavir, chloramphenicol, cimetidine, ciprofloxacin, clarithromycin, cyclosporine, delavirdine, diltiazem, diphenhydramine, disulfiram, enoxacin, erythromycin, fluconazole, fluoxetine, fluvoxamine, furanocoumarins (substances in grapefruit juice), indinavir, isoniazid, itraconazole, ketoconazole, metronidazole, mexile-tine, miconazole, nefazodone, omeprazole, paroxetine, propoxyphene, quinidine, ritonavir, sulfamethizole, verapamil, voriconazole, zafirlukast, and zileuton. 

Liston HL, DeVane CL, Boulton DW, et al. Differential time course of cytochrome P450 2D6 enzyme inhibition by fluoxetine, sertraline, and paroxetine in healthy volunteers. J Clin Psychopharmacol 2002 22 169-173. 

Over the past decade there has been a substantial improvement in the ability to predict metabolism-based in vivo drug interactions from kinetic data obtained in vitro. This advance has been most evident for interactions that occur at the level of cytochrome P450 (CYP)-catalyzed oxidation and reflects the availability of human tissue samples, cDNA-expressed CYPs, and well-defined substrates and inhibitors of individual enzymes. The most common paradigm in the prediction of in vivo drug interactions has been first to determine the enzyme selectivity of a suspected inhibitor and subsequently to estimate the constant that quantifies the potency of reversible inhibition in vitro. This approach has been successful in identifying clinically important potent competitive inhibitors, such as quinidine, fluoxetine, and itraconazole. However, there is a continuing concern that a number of well-established and clinically important CYP-mediated drug interactions are not predictable from the classical approach that assumes reversible mechanisms of inhibition are ubiquitous. 

The symptoms may have been due to a direct effect of clarithromycin or else inhibition of hepatic cytochrome P450 metabolism, leading to fluoxetine toxicity. Clarithromycin occasionally causes hallucinations. 

Otton SV, Wu D, Joffe RT, Cheung SW, Sellers EM. Inhibition by fluoxetine of cytochrome P450 2D6 activity. Clin Pharmacol Ther 1993 53 401-9. 

Potential interactions through the cytochrome P450 CYP 2D6 and CYP 3A4 enz)unes can be noted from Tables 19.2a and 19.2b. The combination of drugs that are substrates of the same enzyme creates potential for competitive inhibition of their metabolism with unexpected elevation of plasma concentration. Similarly, potent inhibitors, e.g. fluoxetine and paroxetine (CYP 2D6), fluoxetine and nefazodone (CYP 3A4) and fluvoxamine (CYP 1A2), may cause adverse effects by reducing metabolic breakdown of co-prescribed drugs that are used in standard doses. Antidepressants are commonly prescribed with antipsychotics in a depressive... 

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. 

I With fluoxetine and paroxetine (due to cytochrome P450-2D6, -3A3/4 inhibition) antipsychotics, opiates, TCAs. 

In a few cases, marked extrapyramidal side-effects (akathisia, dystonia, and parkinsonism) have been reported with flupbenazine, perphenazine, sulpiride, and thiothixene when fluoxetine is added to the regimen. The mechanism is speculated to be the result of fluoxetine-induced further suppression of dopaminergic activity in the nigrostriatal pathways (serotonergic stimulation leads to decreased dopamine release), in addition to increases in their plasma concentration. Fluoxetine has been shown to increase haloperidol serum levels by about 20%, presumably via inhibition of cytochrome P450 enzymes. Fluoxetine can increase the risk of seizure induction when added to clozapine due to an increase in clozapine serum levels, or by additive effects. Concomitant treatment with fluoxetine and risperidone is associated with a mean 4-fold increase in the plasma concentration of risperidone. ... 

Drugs such as cimetidine, feibamate, fluconazole, fluoxetine, fluvoxamine, omeprazole, teniposide, tolbutamide, and troglitazone that inhibit the cytochrome P450 enzyme CYP2C19 thereby inhibit the metabolism of topiramate and can increase its serum levels. 

An increase (about 2-fold) in serum levels of tricyclic antidepressants (TCAs) is found in up to 10% of treated patients (most established with clomipramine and nortriptyline). Such serum level abnormalities are not observed with desipramine. Marked extrapyramidal side-effects have been reported (a few cases only) with haloperidol when fluoxetine is added to the regimen. Fluoxetine and paroxetine have been shown to increase haloperidol serum levels (by about 20%), presumably via inhibition of cytochrome P450 enzymes. 

A sampling of commonly used drugs with cytochrome P450-mediated metabolism inhibited by ketoconazole or other azoles includes chlordiazepoxide, cisapride, cyclosporine, didanosine, fluoxetine, loratadine, lovastatin, methadone, nifedipine, phenytoin, quinidine. theophylline, verapamil, warfarin, and zolpidem. 

The evidence suggests that fluoxetine and fluvoxamine inhibit the metabolism of carbamazepine by the liver (presumably by inhibiting the cytochrome P450 isoenzyme CYP3A4) so that its loss from the body is reduced, leading to a rise in its serum levels. - ... 

An in vitro investigation found that fluoxetine and fluvoxamine inhibited the metabolism of phenytoin by the cytochrome P450 isoenzyme CYP2C9 in human liver tissue. This would presumably lead to a rise in serum phenytoin levels. In this study, sertraline was a weaker inhibitor of CYP2C9, and was considered less likely to interact with phenytoin.A similar study also suggested that the risk of interaction was greatest for fluoxetine, and less likely with sertraline and paroxetine. Sertraline plasma levels may be reduced because of enzyme induction by phenytoin which would increase its metabolism and clearance from the body. ... 

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. "... 

The concurrent use of fluoxetine 60 mg daily has been found to reduce the clearance of alprazolam 1 mg four times daily by about 21% and to increase its plasma levels by about 30%. These changes were accompanied by increased psychomotor impairment. This appears to be due to reduced alprazolam metabolism. Another study also reported impaired alprazolam metabolism, considered to be due to the inhibition of cytochrome P450 isoenzyme CYP3A4 by fluoxetine, although no significant changes in alprazolam pharmacodynamics were found. ... 

Fluoxetine and paroxetine inhibit the cytochrome P450 isoenzyme CYP2D6 by which risperidone is metabolised, hence risperidone levels rise. This can lead to extrapyramidal adverse effects and, it has been suggested, the increased prolactin levels and gynaecomastia seen in one patient. Sertraline is thought to have a dose-dependent effects on CYP2D6 inhibition. ... 

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