Nefazodone metabolites

In a study in 12 healthy subjects, nefazodone 200 mg twice daily was given alone for 5 days. After a washout period, lithium was given for 11 days, in escalating doses from 250 mg twice daily to 500 mg twice daily. When therapeutic steady-state lithium levels were achieved nefazodone 200 mg twice daily was added for 5 days. The pharmacokinetics of both nefazodone and lithium were unaltered by concurrent use, although there were some small changes in the pharmacokinetics of the nefazodone metabolites. However, since the combination was well tolerated, no dosage adjustments were considered necessary on concurrent use. ... 

Desipramine. The manufacturer of nefazodone reported that desipramine 75 mg daily did not change the pharmacokinetics of nefazodone 150 mg twice daily, but levels of the nefazodone metabolite, meta-chlorophenyl-piperazine, were increased by up to 50%. There was no change in the pharmacokinetics of desipramine or its metabolite. No specific dosage adjustments were said to be required on concurrent use. ... 

Li AC, Shou WZ, Mai TT, Jiang XY. Complete profiling and characterization of in vitro nefazodone metabolites using two different tandem mass spectrometric platforms. Rapid Commun Mass Spectrom 2007 21 4001-4008. 

Li AC, Shou WZ, Mai TT, Jiang X (2007) Complete profiling and characterization of in vitro nefazodone metabolites using two different tandem mass spectrometric platforms. Rapid Commun Mass Spectrom 21(24) 4001 008. doi 10.1(X)2/rcm.3303 Liao W, Draper WM, Perera SK (2008) Identification of unknowns in atmospheric pressure ionization mass spectrometry using a mass to structure search engine. Anal Chem 8(K20) 7765—7777. doi 10.1021/ac801166z... 

In our laboratories, a cycle time of 90 sec can be achieved with a dilution factor of 1 25 for a given sample concentration, allowing the purity and identity control of two and a half 384-well microtiter plates per day. The online dilution eliminated an external step in the workflow and reduced the risks of decomposition of samples in the solvent mixture (weakly acidic aqueous solvent) required for analysis. Mao et al.23 described an example in which parallel sample preparation reduced steps in the workflow. They described a 2-min cycle time for the analysis of nefazodone and its metabolites for pharmacokinetic studies. The cycle time included complete solid phase extraction of neat samples, chromatographic separation, and LC/MS/MS analysis. The method was fully validated and proved rugged for high-throughput analysis of more than 5000 human plasma samples. Many papers published about this topic describe different methods of sample preparation. Hyotylainen24 has written a recent review. 

These include trazodone and a derivative of its metabolite nefazodone, both of which are strongly sedative, an effect which has been attributed to their potent alpha-1 receptor antagonism rather than to any antihistaminic effects. A main advantage of these drugs in the treatment of depression is that they appear to improve the sleep profile of the depressed patient. Their antidepressant activity is associated with their weak 5-HT reuptake inhibition and also a weak alpha-2 antagonism. However, unlike most of the second-generation antidepressants, neither drug is effective in the treatment of severely depressed patients. Furthermore, there is some evidence that trazodone can cause arrythmias, and priapism, in elderly patients. 

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. 

Lactation It is not known whether nefazodone or its metabolites are excreted in breast milk. 

Hepatic cirrhosis In patients with cirrhosis of the liver, the AUC values of nefazodone and its metabolite HO-NEF were increased by about 25%. 

Dose-dependent sustained diastolic hypertension Nausea, dry mouth, dizziness, constipation orthostatic hypotension sedation priapism (trazodone only) mCPP, an anxiogenic metabolite of nefazodone, can accumulate during CYP2D6 inhibition Drowsiness (greater at low doses ) Appetite/weight gain... 

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). 

However, its relative weak affinity for these uptake pumps has raised questions as to whether either of these mechanisms is relevant to its antidepressant activity. The combined plasma concentration of bupropion and its three active metabolites are consistent with the conclusion that the inhibition of both of these uptake pumps likely occurs under clinically relevant dosing conditions. For comparison purposes, the combined levels of bupropion and its metabolites are in microgram per milliliter range versus the nanogram per milliliter range for almost all other antidepressants (163). The only other antidepressant that achieves plasma concentration comparable with bupropion is nefazodone and its metabolites (164). That observation is also consistent with the relatively weak in vitro affinity of nefazodone and its metabolites for 5-HT2,a receptors and the serotonin uptake pump. 

Nefazodone is biotransformed into two other metabolites, hydroxynefazodone (OH-NEF) and triazolodione ( 312). These latter two metabolites cannot be formed from trazodone because of structural differences between it and nefazodone. OH-NEF is an active metabolite with a pharmacological profile similar to that of the parent drug and is believed to contribute comparably to the overall clinical response. Its half-life is also approximately 4 hours. 

Triazolodione has only part of the pharmacological activity of nefazodone, being a relatively pure 5-HT 2a antagonist blocker. Thus, it would be expected to produce only part of the overall pharmacological effects of the parent drug. Nonetheless, this metabolite may be clinically important because it accumulates in concentrations 10 times that of nefazodone because of its considerably longer half-life (i.e., 18 to 33 hours). 

Mayol R, Cole C, Luke G, et al. Characterization of the metabolites of the antidepressant drug nefazodone in human urine and plasma. Drug Metab Dispos 1994 22 304-311. 

Franc J, Duncan G, Farmen R, et al. High-perfomance liquid chromatographic method for the determination of nefazodone and its metabolites in human plasma using laboratory robotics. J Chromatogr Biomed Appi 1991 570 129-138. 

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 is chemically related to trazodone. Its primary metabolites, hydroxynefazodone and m-cpp are both inhibitors of the 5-HT2 receptor. Nefazodone received an FDA black box warning in 2001 implicating it in hepatotoxicity, including... 

Nefazodone is a weak inhibitor of both SERT and NET but is a potent antagonist of the postsynaptic 5-HT2A receptor, as are its metabolites. Trazodone is also a weak but selective inhibitor of SERT with little effect on NET. Its primary metabolite, m-cpp, is a potent 5-HT2 antagonist, and much of trazodone s benefits as an antidepressant might be attributed to this effect. Trazodone also has weak-to-moderate presynaptic -adrenergic blocking properties and is a modest antagonist of the Hi receptor. 

Nefazodone Inhibition of 5- 2 receptor nefazodone also blocks SERT weakly Trazodone forms a metabolite (m-cpp) that blocks 5-HT2A,2C receptors Major depression sedation and hypnosis (trazodone) Relatively short half-lives active metabolites Toxicity Modest receptor blockade (trazodone) Interactions Nefazodone inhibits CYP3A4... 

Several LC-MS and LC-MS/MS methods were developed in plasma for only one antidepressant and, sometimes, its major metabolite(s) to perform pharmacokinetic, bioavailability, or bioequivalence studies. Analytical methods developed for these purposes require very low LLOQ values and, usually, narrow linear ranges covering the low range of the therapeutic concentrations are validated. In this context, several methodologies were described for the determination of fluoxetine [94, 95, 98-100], paroxetine [44, 71, 85, 101, 102], venlafaxine [48, 61, 64, 86, 103,104], sertraline [62, 68, 83], citalopram [46, 89] and escitalopram [105], mianserine [106, 107], mirtazapine [42], trazodone [84], nefazodone [51, 81], duloxetine [47, 50, 73], and bupropion [43], Deuterated analogues of the analyte of interest or of other drugs were employed by few authors as IS [43, 61, 73, 81, 85, 99] however, in most of these methods, another antidepressant or other therapeutic drug was used for this purpose. 

Mao Y, Huang MQ, Xia YQ et al (2007) High-throughput quantitation of nefazodone and its metabolites in human plasma by high flow direct-injection LC-MS/MS. J Pharm Biomed Anal 43 1808-1819... 

Concentrations of nefazodone and its metabolites can be increased by fluoxetine and paroxetine (SEDA-20, 9). Combinations of serotonin agents produce serotonin toxicity, and a case of serotonin syndrome occurred when nefazodone (200 mg/day) was combined with fluoxetine (40 mg/day) in a 50-year-old man (109). The toxic symptoms settled 3 days after withdrawal of both antidepressants. 

A 40-year-old man had taken clozapine 450 mg/day and risperidone 6 mg/day for several years. Nefazodone 200 mg/day was added in an attempt to improve persistent negative symptoms, and after a week the dosage was increased to 300 mg/day. One week later, he reported anxiety and dizziness and was hypotensive. The combined concentrations of clozapine and its active metabolite norclozapine had increased from 309 ng/ml before nefazodone to 566 ng/ml. The nefazodone dosage was reduced to 200 mg/day and the anxiety, dizziness, and hypotension resolved over the next 7 days. At the same time plasma concentrations of clozapine and norclozapine fell to 370 ng/ml. 

In 12 healthy volunteers, there were no clinically significant alterations in blood concentrations of lithium or nefazodone and its metabolites when the drugs were co-... 

In 12 healthy volunteers, there were no clinically significant alterations in blood concentrations of lithium or nefazodone and its metabolites when the drugs were coadministered (587). The addition of lithium for 6 weeks to nefazodone in 14 treatment-resistant patients produced no serious adverse effects and no dropouts (588). Lithium augmentation of nefazodone in 13 treatment-resistant depressed patients was associated with a variety of annoying adverse effects, but none led to treatment withdrawal (589). 

Since a metabolite of nefazodone, mCPP, is a substrate of CYP450 2D6, combination of 2D6 inhibitors with nefazodone will raise mCPP levels, leading to stimulation of 5HT2C receptors and causing dizziness and agitation... 

The pharmacokinetic interaction of nefazodone 200 mg bd with steady-state carbamazepine has been investigated in 12 healthy men (103). Nefazodone increased the steady-state plasma AUC of carbamazepine by 23% and reduced the AUC of active carbamazepine-10,ll-epoxide by 20%. The steady-state AUC of nefazodone fell 14-fold and the AUCs of its metabolites (hydroxynefazodone, metachlorophenylpiperazine, and triazoledione) also fell significantly. Thus nefazodone had a small inhibitory effect on carbamazepine metabolism, while carbamazepine greatly increased the metabolism of nefazodone. 

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