Absorption, Distribution and Excretion
The pharmacokinetics of nomifensine were studied in 6 subjects aged 23-41 yr, after single oral administration of two 50 mg capsules of nomifensine maleate (Nomival) and 100 mg intravenous injection, and after 2 wk of oral daily administration of 150 mg in capsule form. The determination of free and total nomifensine in plasma and urine was performed by HPLC. Nomifensine was rapidly absorbed from the gastrointestinal tract and peak concentration of free nomifensine was reached at 1.13 hr. The elimination half life after single dose was about 4 hr regardless of the route of administration. Nomifensine was extensively distributed in body fluids and tissues, with an apparent volume of distribution of 8.69 L/kg. The AUC of free nomifensine after oral dosing was only 26.5% of that after intravenous infusion. Absorption from the gastrointestinal tract was complete, and the AUCs of total nomifensine were equal after all treatments. The AUC of free nomifensine decreased substantially and the elimination half life was shortened after a 2-wk dosing period. It was concluded that the main reason for limited bioavailability seems to be extensive first-pass metabolism during the absorption process and that a marked induction of the metabolizing enzymes is suggested; therefore, an increase in nomifensine dosage may be needed in some patients to maintain a full therapeutic effect. /Nomifensine maleate/
The pharmacokinetics of nomifensine were assessed in 12 healthy men and women following single 100 mg oral doses of nomifensine maleate (Merital). Mean plasma half-life of unconjugated nomifensine was 1.9 hr and for total nomifensine was 4.1 hr. The mean peak plasma concentration of unconjugated nomifensine was 130 + or - 36.5 ug/L for men and 38 + or - 9.7 ug/L for women, a significant difference. No differences between males and females were observed for peak total nomifensine plasma concentrations. ... Oral clearance was higher in women than men as were the respective volumes of distribution.
The disposition of radioactivity from (14)C-nomifensine has been compared in pregnant and non-pregnant female rats by examining plasma profiles, the qualitative tissue distribution (whole body autoradiography) and the quantitative tissue distribution of radioactivity. The clearance of radioactivity of (14)C-nomifensine from the plasma of pregnant and non-pregnant rats was similar and was complex with secondary peaks and plateaux after both oral and intravenous dosing. Maximum plasma levels (mean +/- S.D., 0.20 +/- 0.05 and 0.22 +/- 0.02 ug equivalents nomifensine/mL plasma for pregnant and non-pregnant rats respectively) occurred at 30 to 45 min after oral dosing. The biological half-life of radioactivity in plasma was between 4 and 5 hr for both routes of administration, although there was an additional rapid initial phase (half life approx. 20 min) after intravenous dosing. Whole body autoradiography also showed a very similar tissue distribution pattern of radioactivity between pregnant and non-pregnant rats with extensive distribution from blood into tissue. Only traces of radioactivity from (14)C-nomifensine were seen to cross the placenta into the fetuses of 15-day pregnant rats and these rapidly cleared with time. Slightly higher amounts were seen to cross the fetuses of 18-day pregnant rats and radioactivity was seen in the fetal brain, heart, liver and lung. Quantitative tissue distribution studies confirmed these qualitative findings. The biological half-life of radioactivity in both adult and fetal tissues was approximately 5 hr, except for adult livers where a longer half-life of radioactivity of approximately 10 hr was found.
Nomifensine (1 and 5 mg/kg) was administered to dogs orally and intravenously. The pharmacokinetics of the drug was evaluated. Nomifensine was rapidly absorbed from the gastro-intestinal tract reaching maximum concentration at 0.5-1 hr. The peak levels were directly proportional to the doses administered. The elimination half-life was 6 hr and only very small amounts were found in blood at 24 hr after administration. The apparent volume of distribution (Vd) was 120-149 1, suggesting an extensive distribution of the drug throughout body fluids and tissues. The area under the serum concentration-time curve (AUC) obtained after oral administration was significantly smaller than that after intravenous administration indicating incomplete bioavailability of the drug in oral form. The conjugation of nomifensine after the two different administration routes was also studied: the conjugation reaction was in equilibrium at 15 min after oral administration, while after intravenous administration, equilibrium was not reached until 1-1.5 hr. The metabolism of nomifensine occurred in the gastrointestinal membranes and or in the liver during the absorption process; the first-pass effect was marked.
Nomifensine is rapidly absorbed and is widely distributed. After oral administration, peak levels are obtained within one to two hours. It has a rapid elimination half life of two hours and is primarily excreted in the urine, 60% to 65% unchanged, the remainder as metabolites. Nomifensine is excreted in breast milk. Despite the short half life, electroencephalographic studies in humans reveal that maximal central nervous system effects are sustained up to eight hours after the oral administration of 75 or 150 mg of nomifensine. Thus, central effects persist long after the plasma levels of the drug have diminished.

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Metabolism / Metabolites
The metabolism of nomifensine maleate was studied in 6 healthy subjects aged 22-41 yr, after single oral administration of two 50 mg capsules and 100 mg intravenous injection, and after 2 wk of oral daily administration of 150 mg in capsule form. The determination of the 3 main metabolites of nomifensine maleate in plasma and urine was performed by HPLC. The 3 principal metabolites reached maximum plasma concentrations rapidly (1-1.5 hr), less than 10% as a free, unconjugated form and were eliminated rapidly (elimination half life between 6.8 and 9.0 hr). Only very low concentrations of free metabolites were found in plasma after 24 hr. Two wk of dosing had no significant influence on the elimination of half life or AUC values of the metabolites, indicating no change in the hydroxylation and methylation reactions and there were no changes in the conjugation reactions. Nomifensine had a very short half life and no tendency for accumulation after repeated doses. It was concluded that the clinical pharmacokinetic profile of nomifensine maleate is not significantly changed by the kinetic behavior of its 3 main metabolites after the usual maintenance doses. /Nomifensine maleate/
Nomifensine is an antidepressant agent that was removed from use because of a high incidence of hemolytic anemia. It contains an N-methyl-8-aminotetrahydroisoquinoline ring which has the potential to be oxidized to quaternary dihydroisoquinolinium and isoquinolinium ions, albeit such a transformation had not been previously observed. In this report, ... the conversion of nomifensine to a dihydroisoquinolinium ion metabolite by several human enzymes /is demonstrated/. Human liver microsomes supplemented with NADPH generated the dihydroisoquinolinium ion metabolite along with other hydroxylated metabolites, whereas when supplemented with t-butyl peroxide, only the dihydroisoquinolinium ion metabolite was observed. Monoamine oxidase A, but not monoamine oxidase B, catalyzed this reaction, as well as human hemoglobin supplemented with H2O2. Human myeloperoxidase catalyzed this reaction in the presence of H2O2, and activation of the reaction was observed when incubations were conducted in the presence of acetaminophen at concentrations relevant to those measured in humans. The reaction was also observed in human whole blood. The equilibrium between the dihydroisoquinolinium ion and carbinolamine was shown to have a pK of about 11.7.

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Biological Half-Life
The pharmacokinetics of nomifensine were studied in 6 subjects aged 23-41 yr, after single oral administration of two 50 mg capsules of nomifensine maleate (Nomival) and 100 mg intravenous injection, and after 2 wk of oral daily administration of 150 mg in capsule form. ... The elimination half life after single dose was about 4 hr regardless of the route of administration. ... /Nomifensine maleate/
The pharmacokinetics of nomifensine were assessed in 12 healthy men and women following single 100 mg oral doses of nomifensine maleate (Merital). Mean plasma half-life of unconjugated nomifensine was 1.9 hr and for total nomifensine was 4.1 hr.
The disposition of radioactivity from (14)C-nomifensine has been compared in pregnant and non-pregnant female rats ... . The biological half-life of radioactivity in plasma was between 4 and 5 hr for both routes of administration /oral and intravenous/, although there was an additional rapid initial phase (half life approx. 20 min) after intravenous dosing. ... The biological half-life of radioactivity in both adult and fetal tissues was approximately 5 hr, except for adult livers where a longer half-life of radioactivity of approximately 10 hr was found.
Nomifensine (1 and 5 mg/kg) was administered to dogs orally and intravenously. ... The elimination half-life was 6 hr and only very small amounts were found in blood at 24 hr after administration. ...

Interactions
Six epileptic patients (aged 21-28 yr) on either phenytoin and phenobarbital (phenobarbitone) or phenytoin and carbamazepine, and 6 controls (aged 21-25 yr), were given single oral doses of 30 mg mianserin and 100 mg of nomifensine, at least one month apart, to determine if treatment with anticonvulsants would influence the pharmacokinetics of mianserin and nomifensine. The results showed that plasma levels of mianserin and nomifensine were significantly reduced in epileptic patients treated with anticonvulsants.

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Non-Human Toxicity Values
LD50 rat intravenous 72 mg/kg
LD50 mouse oral 260 mg/kg
LD50 mouse intravenous 90 mg/kg
LD50 guinea pig intravenous 264 mg/kg

Nomifensine is an N-methylated tetrahydroisoquinoline carrying phenyl and amino substituents at positions C-4 and C-8, respectively. It has a role as a dopamine uptake inhibitor.
Nomifensine, formerly marketed as Merital capsules, was associated with an increased incidence of hemolytic anemia. The approved application holder removed Merital capsules from the market on January 23, 1986. FDA published a notice of its determination that Merital capsules were removed from the market for safety reasons (see the Federal Register of June 17, 1986 (51 FR 21981)). Approval of the NDA for Merital capsules was withdrawn on March 20, 1992 (see the Federal Register of March 20, 1992 (57 FR 9729)). Also withdrawn from the Canadian and UK markets.
An isoquinoline derivative that prevents dopamine reuptake into synaptosomes. The maleate was formerly used in the treatment of depression. It was withdrawn worldwide in 1986 due to the risk of acute hemolytic anemia with intravascular hemolysis resulting from its use. In some cases, renal failure also developed. (From Martindale, The Extra Pharmacopoeia, 30th ed, p266)

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Mechanism of Action
Nomifensine ... while it resembles the imipramine type agents in many of the pharmacologic tests used in screening potential antidepressive activity, nomifensine is distinct in its potent inhibitory effects on the neuronal reuptake of dopamine. ... Nomifensine's dopaminergic profile is essentially restricted to reuptake blockade. It has no presynaptic effects on dopamine release as would amphetamine and no post synaptic effects on adenylate-cyclase linked dopamine (D-1) receptors as would apomorphine (a dopamine agonist).
In addition to its potent dopaminergic effects, nomifensine has important effects on the noradrenergic system. Nomifensine is more than 20 times as potent as imipramine, and equipotent to desipramine, in inhibiting the neuronal reuptake of norepinephrine. In electrophysiologic studies nomifensine is four times as active, within the locus coeruleus (a major noradrenergic brain nucleus), as desipramine, and nomifensine is 20 times as potent as imipramine with this test system. In accord with such activity, chronic treatment with nomifensine leads to a reduction in the sensitivity of postsynaptic beta-noradrenergic receptors.
Nomifensine has relatively weak alpha-adrenergic blocking effect. In vitro binding studies suggest that nomifensine is six times less potent than imipramine at antagonism of the alpha-1 receptor, but twice as potent at the alpha-2. In this regard, nomifensine has less alpha-blocking activity than trazodone. Based upon these characteristics, both sedation and adverse cardiovascular (eg, hypotensive) effects should not be prominent with nomifensine.
Effects on the serotonergic system are varied. Nomifensine is a weak inhibitor of serotonin reuptake into rat brain synaptosomes, and is 1/300 times as potent as imipramine, and equipotent to desipramine, in this regard. This is confirmed in electrophysiologic studies where nomifensine has extremely weak, although not absent, activity within the dorsal raphe. However, while nomifensine appears to be inactive in serotonergic systems it has some binding affinity for serotonergic receptors; it is as avid as imipramine for the 5-HT 1 receptor, but is less than 1/100 as avid as imipramine for the 5-HT 2 receptor.
For more Mechanism of Action (Complete) data for NOMIFENSINE (6 total), please visit the HSDB record page.

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Therapeutic Uses
Nomifensine, formerly marketed as Merital capsules, was associated with an increased incidence of hemolytic anemia. The approved application holder removed Merital capsules from the market on January 23, 1986. FDA published a notice of its determination that Merital capsules were removed from the market for safety reasons (see the Federal Register of June 17, 1986 (51 FR 21981)). Approval of the NDA for Merital capsules was withdrawn on March 20, 1992 (see the Federal Register of March 20, 1992 (57 FR 9729)). Also withdrawn from the Canadian and UK markets.
Nomifensine, introduced in 1985, is a tetrahydroisoquinoline antidepressant. /No longer approved for use in the US/

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Drug Warnings
Nomifensine, formerly marketed as Merital capsules, was associated with an increased incidence of hemolytic anemia. The approved application holder removed Merital capsules from the market on January 23, 1986. FDA published a notice of its determination that Merital capsules were removed from the market for safety reasons (see the Federal Register of June 17, 1986 (51 FR 21981)). Approval of the NDA for Merital capsules was withdrawn on March 20, 1992 (see the Federal Register of March 20, 1992 (57 FR 9729)). Also withdrawn from the Canadian and UK markets.
The development of sudden fever in 6 women and one man (mean age, 64 yr) during oral nomifensine therapy at usual doses is reported. During original therapy, fever occurred within 2 wk (range, a few hr to 30 days) and sooner during a second treatment (one to 3 days). In 6 cases, the recurrence of the fever closely following the rechallenge is suggestive of a causal relationship and implies a hypersensitivity reaction.
In humans, nomifensine has been found to mildly elevate heart rate but not to affect orthostatic blood pressure, QRS width, QT interval, or the His-bundle electrocardiogram at doses up to 200 mg/day for three weeks.
... Potent dopaminergic activity may induce, or bring out, dyskinetic movements in susceptible individuals as has been described in at least one case.
For more Drug Warnings (Complete) data for NOMIFENSINE (6 total), please visit the HSDB record page.

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Pharmacodynamics
Nomifensine is a dopamine reuptake inhibitor test-marketed in the United States by Hoechst AG (now Novartis) that increases the amount of synaptic dopamine available to receptors by blocking dopamine's re-uptake transporter. Nomifensine is now mainly used in scientific research, particularly in studies involving dopamine release in response to addiction.

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.)