Paroxetine cytochrome P450 inhibition

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). 

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. 

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... 

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

Paroxetine is metabolized by the hepatic cytochrome P450 enzyme CYP2D6. Hence, it is susceptible to pharmacokinetic interaction with drugs that either induce or inhibit this enzyme. 

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. 

Segura H Farre M, Pichini S, Peiro AM, Roset PN, Ramirez A, Ortufio J, Pacifici R, Zuccaro P, Segura J, de la Torre R Contribution of cytochrome P450 2D6 to 3,4-methylenedio> meth-amphetamine disposition in humans use of paroxetine as a metabolic inhibited probe. Clin Pharmacokinet (2005) 44, 649-60. 

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. "... 

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. ... 

Fluoxetine and paroxetine inhibit the cytochrome P450 isoenzyme CYP2D6 thus inhibiting the metabolism of some beta blockers (e.g. propranolol, metoprolol, carvedilol) so that they accumulate, the result being that their effects, such as bradycardia, may be increased. Citalopram and escitalopram may also inhibit CYP2D6. In vitro studies with human liver microsomes found that fluoxetine and paroxetine are potent inhibitors of metoprolol metabolism and fluvoxamine, sertraline and citalopram less potent. However, fluvoxamine also potently inhibits the metabolism of propranolol by CYP1A2. Beta blockers that are not extensively me-... 

Paroxetine has been reported to increase the average steady state plasma concentrations of ranolazine 1.2-fold. Ranolazine is metabolised by the cytochrome P450 isoenzymes CYP2D6, which paroxetine inhibits. However, as CYP2D6 is not the main route of metaholism, only very modest effects are seen, and no dosage adjustment is necessary. ... 

Tacrolimus is metabolised by the cytochrome P450 isoenzyme CYP3A4, which is inhibited by nefazodone, concurrent use therefore results in increased levels of tacrolimus. Paroxetine and sertraline do not have significant effects on CYP3A4 and are therefore not expected to interact with tacrolimus. 

The cytochrome P450 isoenzyme CYP2D6 is inhibited by fluoxetine and paroxetine and CYP1A2 is inhibited by fluvoxamine. Both of these isoenzymes are involved in the metabolism of mirtazapine, which may explain the raised mirtazapine levels reported. 

Not understood. The symptoms that developed with eitalopram or paroxetine and dextromethorphan were attributed by the authors of the reports to the serotonin syndrome, caused by the additive effeets of the SSRIs and dextromethorphan on serotonin transmission. It has also been suggested that paroxetine inhibited the cytochrome P450 isoenzyme CYP2D6, by which dextromethorphan is metabolised, resulting in increased dextromethorphan levels. Fluoxetine also inhibits CYP2D6. ... 

Fluvoxamine, and to a lesser extent fluoxetine, paroxetine, and sertraline, can inhibit the liver metabolism of the methadone (possibly by the cytochrome P450 isoenzymes CYP3A4," CYP2D6,"- and/or CYP1A2" ) thereby allowing it to accumulate in the body. 

Paroxetine is a potent inhibitor of the cytochrome P450 isoenzyme CYP2D6 and inhibits the CYP2D6 mediated formation of the O-demeth-ylated metabolites of tramadol. The reduction in these metabolites may result in reduced analgesia as the opioid effect of tramadol is thought to be mediated mainly by (+)-0-desmethyltramadol. ... 

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