Fluvoxamine 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. 

Mirtazapine does not significantly inhibit hepatic cytochrome P450 enzymes. Additive effects may occur when mirtazapine is combined with other drugs with sedative or vascular effects. Mirtazapine should not be used in combination with an MAOI or within 14 days of discontinuing treatment with an MAOI. When it is combined with fluvoxamine, a potent inhibitor of P450 enzymes— including 1A2, 2D6, and 3A4, which metabolizes mirtazapine—the plasma concentration of mirtazapine may be increased by up to fourfold (AnttUa et al. 2001 Demers et al. 2001). 

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. 

Orlando R, Padrini R, Perazzi M, et al. (2006) Liver dysfunction markedly decreases the inhibition of cytochrome P450 lA2-mediated theophylline metabolism by fluvoxamine. Clin Pharmacol Ther 79 489-499. 

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. 

Drugs that inhibit cytochrome P450 3A4 (e.g., verapamil, dUtiazem, itraconazole, fluvoxamine, nefazodone, and erythromycin) can increase buspirone levels. Rifampin caused a 10-fold reduction in buspirone levels. Buspirone reportedly increases haloperidol levels and elevates blood pressure in patients taking a monoamine oxidase inhibitor (MAOI). 

With the exception of temazepam, which is eliminated by conjugation, all benzodiazepine hypnotics are metabolized by hepatic microsomal oxidation and then undergo glucuronide conjugation. Oxidation may be inhibited in patients with impaired liver function, advanced age, or concurrent use of drugs that inhibit oxidation. Drugs that inhibit the cytochrome P450 3A4 enzyme (e.g., erythromycin, nefazodone, fluvoxamine, and ketoconazole) reduce the clearance of triazolam and increase its plasma concentrations."... 

I With fluvoxamine (due to cytochrome P450-1A2 inhibition) caffeine, clozapine, theophylline. 

Fluvoxamine inhibits the cytochrome P450 liver catabolic enzymes (predominantly this is inhibition of N-demethylation), leading to an increase in tricyclic antidepressant (TCA) serum levels. Plasma levels of several antidepressant drugs (e.g. amitriptyline, clomipramine, desipramine, imipramine, maprotiline, and nortriptyline) have been reported to increase by up to 4-fold during co-administration with fluvoxamine. Fluvoxamine at a daily dose of 50-100 mg causes a 3-4-fold increase in the plasma concentration of mirtazapine. 

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. 

Fluvoxamine 50 mg twice daily for 7 days increased the AUC of a single 200-mg dose of mexiletine by 55%, and decreased the clearance by 37% in 6 healthy subjects. It is likely that fluvoxamine decreases the metabolism of mexiletine by inhibiting the cytochrome P450 isoenzyme CYP1A2, which is partially responsible fortiie metabolism of mexiletine. The large changes in mexiletine AUC suggest that concurrent therapy should be well monitored. 

Although fluvoxamine had no effect on propafenone 5-hydroxylation in vitro it did inhibit propafenone iV-dealkylation via its inhibitory effects on the cytochrome P450 isoenzyme CYP1A2. This isoenzyme has only a minor role in the metabolism of propafenone, but it may assume greater importance in those who have low levels of CYP2D6 ( poor metabolis-ers). Further study is needed. 

Fluvoxamine probably decreases the elearanee of tolbutamide by inhibition of its metabolism by the cytochrome P450 isoenzyme CYP2C9. This mechanism may also partly explain the inerease in plasma levels of... 

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. ... 

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 use of many inhibitors of the cytochrome P450 isoenzyme CYP3A4 with pimozide is contraindicated since they are expected to increase plasma levels of pimozide, which is likely to result in QT prolongation and associated arrhythmias. The manufacturers specifically mention azole antifungals, fluvoxamine, grapefruit juice, nefazodone, protease inhibitors, and zileuton. Drugs that are known to cause clinically relevant CYP3A4 inhibition are listed in Table 1.4 , (p.6). 

The SSRIs can, to varying degrees inhibit the cytochrome P450 isoenzyme CYP2D6 (and fluvoxamine possibly also inhibits CYP3A4) by which pimozide is metabolised. Concurrent use would therefore be expected to lead to raised pimozide levels. 

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-... 

Fluvoxamine and nefazodone are inhibitors of the cytochrome P450 isoenzyme CYP3A4, the main isoenzyme by which ciclosporin is metabolised. Concurrent use can therefore lead to increased ciclosporin levels. Fluoxetine may interact similarly. Citalopram and sertraline do not usually signifrcantly inhibit CYP3A4 and would therefore not be expected to interact. 

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. 

Fluoxetine inhibits the activity of the cytochrome P450 isoenzyme CYP2D6 within the liver so that the metabolism of oxycodone to an aetive metabolite oxymorphone is reduced. The metabolism of hydroeodone and similar opioids may also be affected by CYP2D6 inhibitors, see Opioids Codeine and related drugs + Quinidine , p.l84. Buprenorphine and morphine are not metabolised by CYP2D6, so their metabolism would not be expeeted to be affected by fluoxetine. Buprenorphine is metabolised by CYP3A4 and so fluvoxamine might be expected to inhibit its metabolism to some extent. 

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. 

Sildenafil is principally metabolised by cytochrome P450 isoenzyme CYP3A4, and to a lesser extent by CYP2C9. Fluvoxamine probably raises sildenafil by inhibition of both of these isoenzymes. Grouping all SSRIs and tricyclics together in a retrospective analysis would not be a sensitive enough technique to have picked up this modest effect of fluvoxamine. 

Tizanidine is a substrate of the cytochrome P450 isoenzyme CYP1A2, which undergoes substantial presystemic metabolism by this isoenzyme. Ciprofloxacin appears to inhibit mainly the presystemic metabolism leading to increased absorption, as reflected by the increase in maximum level without a change in elimination half-life. Rofecoxib and fluvoxamine inhibited both presystemic metabolism and the elimination phase. Fluvoxamine, which is a known potent inhibitor of CYP1A2, had the most marked effect. The contraceptive steroids were modest inhibitors of CYP1A2 by comparison. 

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