Pharmacology and pharmacokinetics of milnacipran

Puozzo, C.; Panconi, E.; Deprez, D.

doi:10.1097/00004850-200206001-00004

Cited by 233 publications

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Section: Introductionmentioning

confidence: 98%

“…The PK profile of milnacipran is the same in both CYP2D6 poor metabolizers (PMs) and extensive metabolizers (EMs), and this finding also holds for CYP2C19 PMs and EMs (Puozzo et al, 2005). Limited to no modification of the pharmacokinetic profile is expected when milnacipran is coadministered with fluoxetine (a strong CYP2D6 inhibitor) or carbamazepine (an inducer of CYP2B6, CYP3A4, and several other enzymes) (Puozzo et al, 2002(Puozzo et al, , 2005(Puozzo et al, , 2006.From the perspective of drug-drug interactions, drugs can be viewed as victims (objects) or perpetrators (precipitants) . Milnacipran has low victim potential because its clearance is not heavily dependent on metabolism by a single drug-metabolizing enzyme; hence, its PK profile is not significantly affected by the genetic polymorphisms, P450 inhibitors, or P450 inducers that affect the disposition of other antidepressant drugs.…”

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confidence: 99%

“…Milnacipran is eliminated primarily by renal excretion of the unchanged drug (50 -60%), conjugation to form a carbamoyl glucuronide (ϳ20%), and N-dealkylation by cytochrome P450 (mainly CYP3A4) to N-desethyl milnacipran (ϳ8%) (Puozzo and Leonard, 1996; DeliniStula, 2000;Tsuruta et al, 2000;Puozzo et al, 2005; Forest Research Institute, personal communication). Metabolism by cytochrome P450 plays only a minor role in the elimination of milnacipran (Caccia, 1998;Grzesiak et al, 2000;Sawada and Ohtani, 2001;Puozzo et al, 2002). Consequently, genetic polymorphisms in CYP2D6 and inhibition of this enzyme do not affect the pharmacokinetics of milnacipran (Puozzo et al, 2005), in contrast to the situation with many selective serotonin-reuptake inhibitors and tricyclic antidepressants (Bertilsson et al, 2002;Preskorn et al, 2007).…”

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In Vitro Inhibition and Induction of Human Liver Cytochrome P450 Enzymes by Milnacipran

Paris¹,

Ogilvie²,

Scheinkoenig³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Milnacipran (Savella) inhibits both norepinephrine and serotonin reuptake and is distinguished by a nearly 3-fold greater potency in inhibiting norepinephrine reuptake in vitro compared with serotonin. We evaluated the ability of milnacipran to inhibit and induce human cytochrome P450 enzymes in vitro. In human liver microsomes, milnacipran did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 (IC 50 > 100 M); whereas, a comparator with dual reuptake properties [duloxetine (Cymbalta)] inhibited CYP2D6 (IC 50 ‫؍‬ 7 M) and CYP2B6 (IC 50 ‫؍‬ 15 M) with a relatively high potency. Milnacipran inhibited CYP3A4/5 in a substrate-dependent manner (i.e., midazolam 1-hydroxylation IC 50 Ϸ 30 M; testosterone 6␤-hydroxylation IC 50 Ϸ 100 M); whereas, duloxetine inhibited both CYP3A4/5 activities with equal potency (IC 50 ‫؍‬ 37 and 38 M, respectively). Milnacipran produced no time-dependent inhibition (<10%) of P450 activity, whereas duloxetine produced time-dependent inhibition of CYP1A2, 2B6, 2C19, and 3A4/5. To evaluate P450 induction, freshly isolated human hepatocytes (n ‫؍‬ 3) were cultured and treated once daily for 3 days with milnacipran (3, 10, and 30 M), after which microsomal P450 activities were measured. Whereas positive controls (omeprazole, phenobarbital, and rifampin) caused anticipated P450 induction, milnacipran had minimal effect on CYP1A2, 2C8, 2C9, or 2C19 activity. The highest concentration of milnacipran (30 M; >10 times plasma C max ) produced 2.6-and 2.2-fold increases in CYP2B6 and CYP3A4/5 activity (making it 26 and 34% as effective as phenobarbital and rifampin, respectively). Given these results, milnacipran is not expected to cause clinically significant P450 inhibition or induction.Milnacipran (Savella), which was recently approved for the treatment of fibromyalgia, is a dual reuptake inhibitor of norepinephrine and serotonin, which is distinguished by an approximately 3-fold greater potency in inhibiting norepinephrine reuptake in vitro compared with serotonin reuptake (Vaishnavi et al., 2004). These two neurotransmitters have been shown to exert significant modulatory effects on peripheral and central pain processing (Dubner and Hargreaves, 1989). Selective serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine and venlafaxine are more potent inhibitors of serotonin reuptake than norepinephrine reuptake, whereas the converse is true of milnacipran (Vaishnavi et al., 2004).Milnacipran is well absorbed (85-90%) after oral administration and has linear pharmacokinetics (PK) over the therapeutic dose range (Delini-Stula, 2000). The terminal elimination half-life in plasma is 6 to 8 h, and steady-state levels can be predicted from single-dose PK data, indicating the absence of autoinhibition or autoinduction. Milnacipran is eliminated primarily by renal excretion of the unchanged drug (50 -60%), conjugation to form a carbamoyl glucuronide (ϳ20%), and N-dealkylation by cytochrome P450 (mainly CYP3A4) to N-desethyl milnacipran (ϳ8%) (Puozzo and Leonard, 1996; DeliniStula, 20...

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Section: Introductionmentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

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In Vitro Inhibition and Induction of Human Liver Cytochrome P450 Enzymes by Milnacipran

Paris¹,

Ogilvie²,

Scheinkoenig³

et al. 2009

Drug Metab Dispos

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“…Milnacipran is conjugated to an inactive glucuronide and excreted in the urine as an unchanged drug and conjugate. Enzymes of the CYP class do not play a role in the metabolism of this antidepressant drug so the risk of interactions with drugs metabolized by CYP enzymes is minimal (Puozzo & Panconi, 2002).…”

Section: Pharmacokineticsmentioning

confidence: 99%

Serotonin Noradrenaline Reuptake Inhibitors (SNRIs)

Çelikyurt¹,

Mutlu²,

Ulak³

2012

Effects of Antidepressants

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“…27,28 The bioavailabilty of milnacipran is high (approximately 85% to 90%), and absorption is not affected by food intake. Milnacipran undergoes minimal first-pass metabolism, with approximately 55% of the drug excreted unchanged in urine.…”

Section: Pharmacologymentioning

confidence: 99%

Role and rationale for the use of milnacipran in the management of fibromyalgia

Kranzler¹,

Gendreau

2010

NDT

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Fibromyalgia (FM) is a complex syndrome characterized by chronic widespread musculoskeletal pain which is often accompanied by multiple other symptoms, including fatigue, sleep disturbances, decreased physical functioning, and dyscognition. Due to these multiple symptoms, as well as high rates of comorbidity with other related disorders, patients with FM often report a reduced quality of life. Although the pathophysiology of FM is not completely understood, patients with FM experience pain differently from the general population, most likely due to dysfunctional pain processing in the central nervous system leading to both hyperalgesia and allodynia. In many patients with FM, this aberrant pain processing, or central sensitization, appears to involve decreased pain inhibition within the spinal tract, which is mediated by descending pathways that utilize serotonin, norepinephrine, and other neurotransmitters. The reduced serotonin and norepinephrine levels observed in patients with FM suggest that medications which increase the levels of these neurotransmitters, such as serotonin and norepinephrine reuptake inhibitors (SNRIs), may have clinically beneficial effects in FM and other chronic pain conditions. Milnacipran is an SNRI that has been approved for the management of FM. In clinical trials, treatment with milnacipran for up to 1 year has been found to improve the pain and other symptoms of FM. Because FM is characterized by multiple symptoms that all contribute to the decreased quality of life and ability to function, the milnacipran pivotal trials implemented responder analyses. These utilized a single composite endpoint to identify the proportion of patients who reported simultaneous and clinically significant improvements in pain, global disease status, and physical function. Other domains assessed during the milnacipran trials include fatigue, multidimensional functioning, mood, sleep quality, and patient-reported dyscognition. This review article provides information intended to help clinicians make informed decisions about the use of milnacipran in the clinical management of patients with FM. It draws primarily on results from 2 of the pivotal clinical trials that formed the basis of approval of milnacipran in the United States by the Food and Drug Administration.

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Pharmacology and pharmacokinetics of milnacipran

Cited by 233 publications

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In Vitro Inhibition and Induction of Human Liver Cytochrome P450 Enzymes by Milnacipran

In Vitro Inhibition and Induction of Human Liver Cytochrome P450 Enzymes by Milnacipran

Serotonin Noradrenaline Reuptake Inhibitors (SNRIs)

Role and rationale for the use of milnacipran in the management of fibromyalgia

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