Nefazodone metabolism

Rotzinger, S, Bourin, M, Akimoto, Y, Coutts, RT and Baker, GB (1999) Metabolism of some second and fourth generation antidepressants iprindole, viloxazine, buproprion, mianserin, maprotiline, trazodone, nefazodone and venlafaxine. Cell. Molec. Neurobiol. 19 427 42. 

A similar approach using accurate mass measurements and predictive fragmentation sofiware was also applied for the examination of the human microsomal metabolism of nefazodone using a linear ion trap-orbitrap hybrid mass spectrometer. Based on a single LC-MS run, using data-dependant acquisition, 15 metabolites of nefazodone could be identified in MS and MS/MS with a mass accuracy better than 3 ppm. 

Metaboiism/Excretion- Nefazodone is extensively metabolized after oral administration by less than 1% is excreted unchanged in urine. The mean half-life ranged between 11 and 24 hours. Nefazodone is extensively (more than 99%) bound to human plasma proteins in vitro. 

Tr/azo/obenzocf/azep/nes-Triazolam and alprazolam, metabolized by cytochrome P-450 3A4, have increased plasma concentrations when administered concomitantly with nefazodone. If triazolam is coadministered with nefazodone, a 75% reduction in the initial triazolam dosage is recommended. It is recommended that triazolam not be used in combination with nefazodone. No dosage adjustment is required for nefazodone. 

Antihistamines, nonsedating/Cisapride/Pimozide- Cisapride and pimozide are metabolized by the cytochrome P-450 3A4 isozyme inhibitors of 3A4 can block the metabolism of these drugs, resulting in increased plasma concentrations of parent drug, which is associated with QT prolongation and with rare cases of serious cardiovascular adverse events, including death, because of ventricular tachycardia of the torsades de pointes type. In vitro, nefazodone inhibits 3A4. It is recommended that nefazodone not be used in combination with cisapride or pimozide. 

Potential interaction with drugs that inhibit or are metabolized by cytochrome P-450 (3A4 and 2D6) isozymes Caution is indicated in the combined use of nefazodone with any drugs known to be metabolized by the 3A4 isozyme (in particular, cisapride or pimozide). 

Concurrent use with ketoconazole, itraconazole, and nefazodone, medications that significantly impair the oxidative metabolism of triazolam mediated by cytochrome P-450 3A (CYP3A). 

Nefazodone is rapidly absorbed after oral administration. It undergoes extensive first-pass metabolism in the liver, causing bioavailability to be limited to approximately 20%. Peak plasma levels are achieved between... 

Clinical pharmacology. Following absorption, peak plasma concentrations occur 1-3 hours after oral administration (Franc et al. 1991). Following extensive hepatic metabolism, the bioavailability of nefazodone is between 15% and 23%, after which it is 99% protein bound. Nefazodone reaches steady-state plasma levels in 3 days and is eliminated from the body within 24 hours, reflecting its half-life of 2-4 hours (Franc et al. 1991). Therapeutic doses in young adults have been found to range from 100 to 300 mg twice daily (E. Fontaine 1994). Lower doses are recommended in patients with concomitant liver disease and the elderly, as plasma concentrations can be double those seen in younger patients. 

Coadministration with most medications that are metabolized by CYP 3A3/4 should be undertaken with caution, and the doses of the other medications that are CYP 3A3/4 substrates (see Table 1-1) should be reduced. The interaction between nefazodone and MAOIs has not yet been evaluated, but it may be as dangerous as... 

Buspirone is metabolized by CYP 3A3/4. Therefore, the initial dose should be lower in patients who are also taking medications known to inhibit these enzymes, such as nefazodone. 

Eszopiclone is metabolized in the liver by CYP 3A4. Eszopiclone should not be used in patients with severe hepatic impairment. Dose adjustment and caution are recommended in patients taking enzyme inhibitors such as ketoconazole, ciprofloxacin, erythromycin, iso-niazid, and nefazodone. Other sedative-hypnotics are not recommended with administration of this medication. 

In contrast to anticonvulsants and alcohol, drugs such as bupropion, fluoxetine, fluvoxamine, nefazodone, quinidine, paroxetine, and some antipsychotics can inhibit specific CYP enzymes (7, 11, 36, 37, 41, 42, 43 and 44). Thus, TCAs, certain BZDs, bupropion, some steroids, and antipsychotics can all have their metabolism inhibited by drugs such as fluoxetine. For example, fluoxetine at 20 mg/day produces on average a 500% increase in the levels of coprescribed drugs which are principally dependent on CYP 2D6 for their clearance. That can lead to serious or even life-threatening toxicity if the drug has a narrow therapeutic index and the dose is not adjusted for the change in clearance caused by the coadministration of fluoxetine. 

First-pass metabolism (first-pass effect) The passage of the drug from the portal circulation into hepatocytes and conversion there into metabolites. These metabolites may have a pharmacological profile different from that of the parent drug. They are typically then excreted by the hepatocytes into the biliary system and pass back into the small bowel where enterohepatic recirculation may occur (e.g., benzodiazepines, bupropion, nefazodone, neuroleptics, tricyclic antidepressants). 

Phenytoin, an enzyme inducer, can reduce clozapine plasma levels. There have been two reported cases of risperidone causing an increase in clozapine plasma levels however, because this agent is not an inhibitor of 1A2, the mechanisms for this increase are unclear. Nefazodone administered with clozapine has had minimal effects on clozapine s metabolism (329). 

Nefazodone has appreciable nonlinear pharmacokinetics because of its metabolism by and inhibition of CYP3A3/4 ( 313). At doses of 200 mg per day, nefazodone undergoes an extensive first-pass metabolism such that its bioavailability is only approximately 20%. At doses of 400 mg per day, its bioavailability is appreciably higher, as are its plasma drug levels. This phenomenon is most likely due to inhibition of its own first-pass metabolism by CYP 3A/4. For this reason, dose-dependent effects of nefazodone can increase nonlinearly with higher doses. 

Because most antidepressants require oxidative metabolism as a necessary step in their elimination, they can be the target of a pharmacokinetic drug-drug interaction, as well as the cause. The CYP enzymes mediating the biotransformation of the various antidepressants are also shown in Table 7-30. CYP 1A2 and 3A3/4 are induced by anticonvulsants such as barbiturates and carbamazepine. As expected, coadministration of these anticonvulsants has been shown to lower plasma levels of TCAs and would be predicted to have the same effect on nefazodone, sertraline, and venlafaxine. 

Nefazodone substantially decreases the clearance rate for triazolam, which results in a 400% increase in triazolam s serum levels (131). Erythromycin can also interfere with the metabolism of triazolam, resulting in decreased clearance and increased plasma levels, possibly causing toxicity. Troleandomycin and other macrolide antibiotics, such as clarithromycin, flurithromycin, josamycin, midecamycin, or roxithromycin, also may inhibit triazolam s metabolism (132). The coadministration of itraconazoie and triazolam can produce a marked elevation of triazolam plasma levels associated with statistically significant impairment of psychomotor tests and a prolongation of other effects (e.g., amnesia, lethargy, and confusion) for hours after awakening ( 133). 

With the important exception of additive effects when combined with other CNS depressants, including alcohol, BZDs interact with very few drugs. Disulfiram (see the section The Alcoholic Patient in Chapter 14) and cimetidine may increase BZD blood levels, and diazepam may increase blood levels of digoxin and phenytoin. Antacids may reduce the clinical effects of clorazepate by hindering its biotransformation to desmethyidiazepam. Coadministration of a BZD and another drug known to induce seizures may possibly increase seizure risk, especially if the BZD is abruptly withdrawn. Furthermore, as noted earlier, important interactions have been reported among nefazodone, erythromycin, troleandomycin, and other macrolide antibiotics, as well as itraconazole. In each case, metabolism is inhibited, and triazolam levels can increase significantly. 

BZD hypnotics such as midazolam and triazolam are primarily metabolized via the P450 3A3/4 microenzyme system. Other BZDs often used as hypnotics, such as diazepam, can also be metabolized by CYP 33/4 and CYP 2C19. Any drugs that act as inhibitors or inducers of these isoenzymes could increase or decrease BZD levels, respectively (350). Thus, ketoconazole, macrolide antibiotics (e.g., erythromycin), SSRIs (e.g., fluoxetine-norfluoxetine and fluvoxamine), and other antidepressants (especially nefazodone) may decrease clearance and increase BZD levels to potentially toxic ranges. Conversely, rifampacin, CBZ, and dexamethasone may increase clearance and decrease BZD levels to potentially subtherapeutic ranges. 

The SSRIs, venlafaxine, or nefazodone may be reasonable alternatives to earlier generation antidepressants because of their less problematic side effect profiles (486). The propensity to increase activity, the lack of sedation, gastrointestinal symptoms, and alterations in blood pressure are potential complications, however. Given AIDS-induced altered metabolism, for many of these agents, TDM may be helpful in establishing an effective, nontoxic dose. 

The risk of myopathy appears to be increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Lovastatin is metabolized by the CYP isoform 3A4. Certain drugs, that share this metabolic pathway can raise the plasma levels of lovastatin and may increase the risk of myopathy. These include cyclosporine, itraconazole, ketoconazole and other antifungal azoles, the macrolide antibiotics erythromycin and clarithromycin, HIV protease inhibitors, the antidepressant nefazodone, or large quantities of grapefruit juice (greater than 1 quart daily)... 

Buspirone is rapidly absorbed orally but undergoes extensive first-pass metabolism via hydroxylation and dealkylation reactions to form several active metabolites. The major metabolite is l-(2-pyrimidyl)-piperazine (1-PP), which has K2-adrenoceptor-blocking actions and which enters the central nervous system to reach higher levels than the parent drug. It is not known what role (if any) 1-PP plays in the central actions of buspirone. The elimination half-life of buspirone is 2-4 hours, and liver dysfunction may slow its clearance. Rifampin, an inducer of cytochrome P450, decreases the half-life of buspirone inhibitors of CYP3A4 (eg, erythromycin, ketoconazole, grapefruit juice, nefazodone) can markedly increase its plasma levels. 

Nefazodone [NP] Possibly decreased metabolism of cisapride by CYP3A4 possible ventricular arrhythmia. 

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. 

Since benzodiazepines are metabolized by the cytochrome P450 family of isozymes,1 potential inhibitors of these may produce significant increases in blood concentrations of benzodiazepines. An example of this inhibition is the drug midazolam, administered as a presurgical anesthetic. Lam et al.11 reported a mean increase in the area under the curve of midazolam by ketoconazole (772%) and nefazodone (444%) in a group of 40 healthy human subjects administered 200 mg ketoconazole per day and 400 mg nefazodone per day. The authors concluded that caution should be exercised when use of midazolam is warranted with potent CYP3A4 inhibitors.11... 

Peterman, S. M., Duczak, N., Jr., Kalgutkar, A. S., Lame, M. E., and Soglia, J. R. (2006). Application of a linear ion trap/orbitrap mass spectrometer in metabohte characterization studies Examination of the human liver microsomal metabolism of the non-tricyclic antidepressant nefazodone using data-dependent accurate mass measurements. J. Am. Soc. Mass Spectrom. 17 363-375. 

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