Absorption, Distribution and Excretion
This study investigated the pharmacokinetics of nomifenxin in six subjects aged 23–41 years. Subjects received a single oral dose of two 50 mg nomifenxin maleate capsules (Nomival), a single intravenous injection of 100 mg, or a two-week course of 150 mg nomifenxin capsules orally. Plasma and urine concentrations of free and total nomifenxin were determined using high-performance liquid chromatography (HPLC). Nomifenxin is rapidly absorbed from the gastrointestinal tract, with peak concentrations of free nomifenxin reached at 1.13 hours. The elimination half-life after a single dose is approximately 4 hours, regardless of the route of administration. Nomifenxin is widely distributed in body fluids and tissues, with an apparent volume of distribution of 8.69 L/kg. The AUC of free nomifenxin after oral administration was only 26.5% of that after intravenous infusion. Gastrointestinal absorption was complete, and the AUC of total nomifenxin was identical after all treatments. Two weeks after administration, the AUC of free nomifenxin significantly decreased, and the elimination half-life was shortened. The conclusion is that the main reason for the limited bioavailability appears to be extensive first-pass metabolism during absorption, suggesting significant induction by metabolic enzymes; therefore, some patients may require an increased dose of nomifenxin to maintain complete therapeutic efficacy. /Nomifenxin Maleate/
This study evaluated the pharmacokinetics of a single oral dose of 100 mg nomifenxin maleate (Merital) in 12 healthy men and women. The mean plasma half-life of free nomifenxin was 1.9 hours, and the mean plasma half-life of total nomifenxin was 4.1 hours. The mean peak plasma concentration of free nomifenxin was 130 ± 36.5 μg/L in men and 38 ± 9.7 μg/L in women, a significant difference. There was no difference in the peak plasma concentration of total nomifenxin between men and women. …Oral clearance and volume of distribution were higher in women than in men. The distribution of (14)C-Nomifensine radioactive material in pregnant and non-pregnant female rats was compared by detecting plasma concentration curves, qualitative tissue distribution (whole-body autoradiography), and quantitative tissue distribution. The clearance of 14C-Nomifensine radioactivity in the plasma of pregnant and non-pregnant rats was similar, exhibiting complex curves with secondary peaks and plateaus after both oral and intravenous administration. The maximum plasma concentration was reached 30 to 45 minutes after oral administration (0.20 ± 0.05 μg Nomifensine equivalents/mL plasma in pregnant and non-pregnant rats, respectively, mean ± standard deviation). The plasma radiobiological half-life was 4 to 5 hours for both administration routes, but an additional rapid initial phase (half-life of approximately 20 minutes) was observed after intravenous administration. Whole-body autoradiography showed very similar radioactive tissue distribution patterns in pregnant and non-pregnant rats, with widespread distribution of radioactive material in both blood and tissues. In female rats at 15 days of gestation, only trace amounts of 14C-Nomifensine radioactive material were observed to cross the placenta into the fetus, and this radioactive material was rapidly eliminated over time. In female rats at 18 days of gestation, slightly higher levels of radioactive material were observed to cross the placenta into the fetus, and the radioactive material was detected in the fetal brain, heart, liver, and lungs. Quantitative tissue distribution studies confirmed these qualitative results. Except for the liver of adult rats, the biological half-life of the radioactive material in adult rat and fetal tissues was approximately 5 hours, with a longer half-life of approximately 10 hours in the liver of adult rats. The pharmacokinetics of Nomifensine were evaluated by oral and intravenous administration (1 and 5 mg/kg) to dogs. Nomifensine is rapidly absorbed from the gastrointestinal tract, reaching maximum concentrations within 0.5–1 hour. Peak concentrations are proportional to the administered dose. The elimination half-life is 6 hours, and only trace amounts of the drug are detectable in the blood 24 hours after administration. The apparent volume of distribution (Vd) is 120-149 liters, indicating widespread distribution of the drug in body fluids and tissues. The area under the serum concentration-time curve (AUC) after oral administration is significantly smaller than that after intravenous administration, indicating incomplete bioavailability after oral administration. The binding of nomifenxin after two different routes of administration was also investigated: the binding reaction reached equilibrium 15 minutes after oral administration, while it took 1-1.5 hours after intravenous administration to reach equilibrium. Nomifenxin is primarily metabolized in the gastrointestinal mucosa and/or liver during absorption; the first-pass effect is significant. Nomifenxin is rapidly absorbed and widely distributed. After oral administration, peak plasma concentrations are reached within 1-2 hours. The elimination half-life of nomifenxin is only two hours, and it is mainly excreted in the urine, with 60% to 65% excreted unchanged and the remainder as metabolites. Nomifenxin can be secreted into breast milk. Despite its short half-life, human electroencephalogram (EEG) studies have shown that the maximum effect on the central nervous system following oral administration of 75 or 150 mg of nomifenxin can last up to eight hours. Therefore, even with decreased plasma drug concentrations, the central nervous system effects can persist for a long time.

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Metabolism/Metabolites
This study investigated the metabolism of nomifenxin maleate in six healthy subjects aged 22 to 41 years. Subjects received a single oral dose of two 50 mg capsules, an intravenous injection of 100 mg, and a two-week course of 150 mg capsules. The three major metabolites of nomifenxin maleate were determined in plasma and urine using high-performance liquid chromatography (HPLC). The three major metabolites rapidly reached peak plasma concentrations (1–1.5 hours), with less than 10% in the free, unbound form, and were rapidly eliminated (elimination half-life of 6.8–9.0 hours). After 24 hours, only very low concentrations of the free metabolites were detected in plasma. Two weeks of dosing had no significant effect on the elimination half-life or AUC of the metabolites, indicating that hydroxylation, methylation, and binding reactions remained unchanged. Nomifenxin has a very short half-life and shows no tendency to accumulate after repeated dosing. The conclusion is that at conventional maintenance doses, the clinical pharmacokinetic characteristics of nomifenxin maleate are not significantly altered by the kinetic behavior of its three major metabolites. /Nomifenxin Maleate/
Nomifenxin is an antidepressant that was discontinued due to its high incidence of hemolytic anemia. It contains an N-methyl-8-aminotetrahydroisoquinoline ring, which has the potential to be oxidized to quaternary ammonium dihydroisoquinolineonium and isoquinolineonium ions, although this conversion had not been previously observed. This report confirms that nomifenxin is converted to the dihydroisoquinolineonium ion metabolite by a variety of human enzymes. Human liver microsomes with added NADPH generated dihydroisoquinoline ion metabolites and other hydroxylated metabolites, while only dihydroisoquinoline ion metabolites were observed with the addition of tert-butyl peroxide. Monoamine oxidase A (but not monoamine oxidase B) and human hemoglobin with added H₂O₂ catalyzed the reaction. Human myeloperoxidase catalyzed the reaction in the presence of H₂O₂, and activation was observed when incubated with acetaminophen in a concentration-dependent manner. The reaction was also observed in human whole blood. The pKa of the equilibrium between dihydroisoquinoline ions and methanolamine is approximately 11.7.

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Biological half-life
This study conducted a pharmacokinetic study of nomifentanil in six subjects aged 23 to 41 years, who received a single oral dose of two 50 mg nomifentanil maleate capsules (Nomival), an intravenous injection of 100 mg, and a two-week oral administration of 150 mg capsules. ...The elimination half-life after a single dose is approximately 4 hours, regardless of the route of administration. .../Nomifenxin Maleate/
The pharmacokinetics of nomifenxin were evaluated in 12 healthy men and women following a single oral dose of 100 mg of nomifenxin maleate (Merital). The mean plasma half-life of unbound nomifenxin was 1.9 hours, and the mean plasma half-life of total nomifenxin was 4.1 hours.
The radiodistribution of ¹⁴C-nomifenxin was compared in pregnant and non-pregnant female rats... The plasma radiobiological half-life was 4 to 5 hours for both routes of administration (oral and intravenous), but there was an additional rapid initial phase (half-life of approximately 20 minutes) after intravenous administration. ...The biological half-life of the radioactive material in adult and fetal tissues, excluding adult animal liver, is approximately 5 hours; the half-life of the radioactive material in adult animal liver is longer, approximately 10 hours. Dogs were administered nomifentanil orally and intravenously (1 and 5 mg/kg, respectively). ...The elimination half-life was 6 hours, and only trace amounts of the drug were detected in the blood 24 hours after administration.

Interactions
Six patients with epilepsy (aged 21–28 years) were administered phenytoin sodium and phenobarbital (phenobarbital) or phenytoin sodium and carbamazepine, respectively, and six controls (aged 21–25 years) were administered 30 mg mianserin and 100 mg nomifenxin orally at intervals of at least one month to determine whether anticonvulsant treatment affected the pharmacokinetics of mianserin and nomifenxin. Results showed that plasma concentrations of mianserin and nomifenxin were significantly reduced in patients with epilepsy receiving anticonvulsant treatment. Non-human Toxicity Values Rat intravenous LD50: 72 mg/kg
Mouse oral LD50: 260 mg/kg
Mouse intravenous LD50: 90 mg/kg
Guinea pig intravenous LD50: 264 mg/kg

Nomifensine is an N-methylated tetrahydroisoquinoline with phenyl and amino substituents at C-4 and C-8, respectively. It is a dopamine reuptake inhibitor. Nomifensine was marketed under the brand name Merital capsules, but it was associated with an increased incidence of hemolytic anemia. On January 23, 1986, Merital capsules were withdrawn from the market. The U.S. Food and Drug Administration (FDA) issued a notice stating that Merital capsules were withdrawn from the market for safety reasons (see Federal Register, June 17, 1986 (51 FR 21981)). On March 20, 1992, the New Drug Application (NDA) for Merital capsules was withdrawn (see Federal Register, March 20, 1992 (57 FR 9729)). It has also been withdrawn from the Canadian and British markets. It is an isoquinoline derivative that prevents dopamine reuptake into the synapse. Maleate was once used to treat depression. Due to the potential for acute hemolytic anemia and intravascular hemolysis, it was withdrawn from the market globally in 1986. Kidney failure can also occur in some cases. (Excerpt from Martindale Pharmacopoeia, 30th edition, p. 266) Mechanism of Action: Nomifensine… While it is similar to imipramines in many pharmacological studies used to screen for potential antidepressant activity, Nomifensine is unique in its potent inhibition of neuronal dopamine reuptake. …Nomifensine's dopaminergic effect is primarily limited to blocking reuptake. It does not produce a presynaptic effect on dopamine release like amphetamine, nor a postsynaptic effect on adenylate cyclase-coupled dopamine (D-1) receptors like apomorphine (a dopamine agonist). In addition to its potent dopaminergic effect, Nomifensine also has significant effects on the norepinephrine system. Nomifensine's potency in inhibiting neuronal norepinephrine reuptake is more than 20 times that of imipramine and comparable to desipramine. Electrophysiological studies have shown that Nomifensine's activity in the locus coeruleus (a major noradrenergic nucleus) is 4 times that of desipramine, and in this test system, Nomifensine's potency is 20 times that of imipramine. Consistent with this activity, long-term use of Nomifensine leads to decreased sensitivity of postsynaptic β-norepinephrine receptors. Nomifensine's alpha-adrenergic blocking effect is relatively weak. In vitro binding studies have shown that Nomifensine's potency against alpha-1 receptors is 6 times lower than that of imipramine, but its potency against alpha-2 receptors is twice that of imipramine. In this respect, Nomifensine's alpha-receptor blocking activity is lower than that of trazodone. Based on these properties, the sedative effects and adverse cardiovascular reactions (e.g., hypotension) of Nomifensine should be minimal. Its effects on the serotonergic system are diverse. Nomifensine is a weak inhibitor of serotonin reuptake into the rat brain synaptosome, with a potency 1/300 that of imipramine and comparable to desipramine. Electrophysiological studies have confirmed that Nomifensine has very weak but not completely absent activity in the dorsal raphe nucleus. However, although Nomifensine appears to be inactive in the serotonergic system, it has some binding affinity for serotonin receptors; its affinity for 5-HT1 receptors is comparable to imipramine, but its affinity for 5-HT2 receptors is less than 1/100 that of imipramine. For more complete data on the mechanisms of action of Nomifensine (6 in total), please visit the HSDB record page. Therapeutic Use: Nomifensine was previously marketed under the brand name Merital capsules and was associated with an increased incidence of hemolytic anemia. The applicant withdrew Merital capsules from the market on January 23, 1986. The U.S. Food and Drug Administration (FDA) issued a notice withdrawing Merital capsules from the market for safety reasons (see the Federal Register, June 17, 1986 (51 FR 21981)). The New Drug Application (NDA) for Merital capsules was withdrawn on March 20, 1992 (see the Federal Register, March 20, 1992 (57 FR 9729)). The product has also been withdrawn from the Canadian and British markets. Nomifenac, marketed in 1985, is a tetrahydroisoquinoline antidepressant. /No longer approved for use in the United States/

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Drug Warning
Nomifenac (formerly marketed as Merital capsules) is associated with an increased incidence of hemolytic anemia. On January 23, 1986, the approved applicant withdrew Merital capsules from the market. The U.S. Food and Drug Administration (FDA) issued a notice withdrawing Merida capsules from the market for safety reasons (see the Federal Register, June 17, 1986 (51 FR 21981)). On March 20, 1992, the New Drug Application (NDA) for Merida capsules was withdrawn (see the Federal Register, March 20, 1992 (57 FR 9729)). The product has also been withdrawn from the Canadian and British markets. The report states that six women and one man (mean age 64 years) experienced sudden onset of fever during treatment with a standard dose of oral nomiphenonex. During the first treatment, fever occurred within two weeks (range: hours to 30 days), while during the second treatment, fever occurred more rapidly (1 to 3 days). In six cases, fever recurred rapidly after re-administration, suggesting a causal relationship and implying hypersensitivity. In humans, Nomifensine has been found to slightly increase heart rate, but at doses up to 200 mg/day for three weeks, it has not affected orthostatic blood pressure, QRS width, QT interval, or His bundle ECG. …The potent dopaminergic activity may induce or exacerbate movement disorders in susceptible individuals, as described in at least one case. For more complete data on Nomifensine (6 of 6), please visit the HSDB record page.

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Pharmacodynamics
Nomifensine is a dopamine reuptake inhibitor, marketed in the US by Hearst (now Novartis). It works by blocking receptors, increasing the amount of dopamine available in the synaptic cleft. Dopamine reuptake transporter. Nomifensine is currently primarily used in scientific research, particularly studies involving dopamine release in addictive responses.

C16H18N2

238.334

238.147

C, 80.63; H, 7.61; N, 11.75

24526-64-5

Nomifensine maleate; 32795-47-4; Nomifensine-d3 maleate; 1795140-41-8

4528

Solid powder

1.1±0.1 g/cm3

378.4±42.0 °C at 760 mmHg

179-181°

164.0±23.0 °C

0.0±0.9 mmHg at 25°C

1.623

2.15

1

2

1

18

272

0

NC1=CC=CC2=C1CN(C)CC2C3=CC=CC=C3

XXPANQJNYNUNES-UHFFFAOYSA-N

InChI=1S/C16H18N2/c1-18-10-14(12-6-3-2-4-7-12)13-8-5-9-16(17)15(13)11-18/h2-9,14H,10-11,17H2,1H3

2-methyl-4-phenyl-3,4-dihydro-1H-isoquinolin-8-amine

HSDB7702; CCRIS9179; HSDB-7702; CCRIS-9179; Nomifensine

2934.99.03.00

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ≥ 100 mg/mL (~419.6 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.49 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (10.49 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)