N-Methyl-gama-(1-naphthalenyloxy)-2-thiophenepropanamine CAS NO.136434-34-9

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Duloxetine hydrochloride Basic information

Pharmacological effects Pharmacokinetics Indications Precautions Drug Interactions Medication of Special Populations Contraindications

Product Name:	Duloxetine hydrochloride
Synonyms:	(S)-DULOXETINE HYDROCHLORIDE;LY-248686;DULOXETINE HCL;DULOXETINE HYDROCHLORIDE;N-methyl-gamma-(1-naphthalenyloxy)-2-thiophenepropanamine, hydrochloride;(RS)Duloxetine HCl;(+)-(S)-N-Methyl-g-(1-naphthyloxy)-2-thiophenepropylamine;(gS)-N-Methyl-g-(1-naphthalenyloxy)-2-thiophenepropanamine
CAS:	136434-34-9
MF:	C18H20ClNOS
MW:	333.88
EINECS:	200-659-6
Product Categories:	APIs;Intermediates & Fine Chemicals;Pharmaceuticals;Isotope Labeled Compounds;Duloxetine;Amines;Aromatics;Heterocycles;Sulfur & Selenium Compounds;SINGULAIR;Other APIs
Mol File:	136434-34-9.mol

Duloxetine hydrochloride Usage And Synthesis

Pharmacological effects	Duloxetine hydrochloride is the salt form of antidepressant drug duloxetine. It was successfully developed by Eli Lilly Company. Its pharmacological effect is the same as duloxetine. Duloxetine hydrochloride is a new kind of selective dual inhibitor of 5 hydroxy trptamine (5-HT) and norepinephrine reuptake, and thus having antidepressant effect, while also having inhibitory effect on the central pain. Its pharmacological characteristic is being able to inhibit neuronal pre-synaptic membrane’s reuptake on 5-hydroxy trptamine and norepinephrine but instead have a low inhibitory effect on the reuptake of dopamine. Duloxetine hydrochloride is indicated for depression and it is effective in treating both endogenous and non-endogenous depression as well as the feeling of pain associated with depression. It has a therapeutic dose of 60mg/d~120mg/d with a good security and fewer adverse reactions with common adverse reactions such as nausea, dry mouth, constipation, poor appetite, fatigue, sleepiness, and increased sweating. Another indication is the pain caused by diabetic neuropathy.  [Product Name] Cymbalta [Alias] LY-264453, LY-248686 [Efficacy] antidepressant drug for treatment of stressful urinary incontinence. [CAS]:136434-34-9 [Development Unit] Japan Shionogi Company, American company Eli-Lilly. Duloxetine is a selective inhibitor for 5-HT and NE reuptake (SSNRI). The exact mechanism of the anti-depression duloxetine and central analgesic effect is not yet clear. It is thought that it is related to its reinforcing effect on the function of 5 hydroxy trptamine (5-HT) and norepinephrine in the central nervous system. The results of the clinical studies have shown that duloxetine is a strong inhibitor of the neuronal 5-HT and NE reuptake and has a relatively weak inhibitory effect on the reuptake of dopamine. In vitro studies have showed that duloxetine has no significant affinity to dopaminergic receptors, adrenergic receptors, cholinergic receptors, histamine receptors, opiate receptors, glutamate receptors, and the GABA receptors. Duloxetine does not inhibit monoamine oxidase. Figure 1: The molecule formula of Duloxetine hydrochloride
Pharmacokinetics	Absorption and Distribution: oral administration of duloxetine hydrochloride enteric-coated capsules can yield a complete absorption with the average lag being two hours before the drug began to be absorbed (TLag). At 6 hours after oral administration, the duloxetine reaches maximum plasma concentration (Cmax) with eating causing no effects on the Cmax, but will delay the peak time to about 6 to 10 hours with slightly lower degree of absorption at about 10%. Compare the evening administration once with morning administration once, the absorption of duloxetine is delayed by 3 hours; apparent elimination increases by one thirds; the apparent volume of distribution is about 1640 L. Duloxetine has a high affinity (> 90%) to the human plasma proteins which mainly binds with albumin and α- acid glycoprotein. There has been no evaluation of whether there exist interactions between duloxetine with other high affinity protein binding drugs. Liver or renal insufficiency does not affect the binding between plasma protein and duloxetine. Metabolism and Excretion: oral administration of C14-labeled duloxetine can be used to determine their in vivo biotransformation and degradation. The plasma duloxetine only account for about 3% of the total radiolabel, suggesting that duloxetine is extensively metabolized with many kinds of metabolites. The major biotransformation pathway of duloxetine includes naphthyl epoxidization after the binding and further oxidation. Among in vitro tests, CYP2D6 and CYPIA2 can both catalyze the epoxidation of naphthyl with the plasma product including glucuronide-bound 4-hydroxy duloxetine and sulfate-bound 5-hydroxy 6-methoxy duloxetine. It has been separated of various kinds of other metabolites from urine with some appearing only in the small elimination metabolic bypass. Only a small amount (about 1% of the oral dose) of non-metabolized duloxetine prototype is detected in the urine with the majority (about 70% of the oral dose) existing in the form of duloxetine metabolic product which is excreted in urine. About 20% of them is excreted through feces. The above information is edited by the Chemicalbook of Dai Xiongfeng.
Indications	It is used for the treatment of depression and the treatment of stress urinary incontinence. In 2004, Japan Shionogi Pharmaceutical Co., Ltd. had obtained the authorization of Eli Lilly Company of US to perform further development on the duloxetine which has dual inhibitory effect on the reuptake of both 5 hydroxy trptamine (5-HT) and norepinephrine (NE). Existing studies have shown that this drug has certain efficacy in treating tension urinary incontinence, depression, and obesity. Currently, clinical trials of the drug for treatment of tension urinary incontinence and depression have all been completed.
Precautions	1. Liver and kidney dysfunction can significantly reduce the metabolism and clearance of duloxetine. Thus it is not recommended for such patients to apply duloxetine.  2. The interaction between duloxetine and alcohol may cause liver damage. Thus it is not generally recommended for the treatment of patients with alcoholism. 3. In the clinical trials, when compared with placebo, duloxetine causes the mean systolic blood pressure increase by 2mmHg, and the average diastolic blood pressure increase by 0.5mmHg. We recommend regular measurement of blood pressure both before and during treatment and therapy.
Drug Interactions	Duloxetine is metabolized through CYP2D6 and CYP1A2 metabolism with moderate inhibition of CYP2D6 but no inhibition and induction effects on CYP1A2 and CYP3A4. We should be cautious when apply it together with other drugs which are also metabolized through CYP2D6 and of narrow therapeutic window (such as: TCAs, Ic antiarrhythmic drugs, and phenothiazines).
Medication of Special Populations	[Medication of Pregnant women and lactating women] It is not clear whether it is safe when applied this drug for pregnant women of pregnancy category. Therefore, for pregnant women, they should weigh both the advantages and disadvantages to decide whether they should administrate this drug. Only with potential benefits higher than risks can they apply it. Otherwise, they should not administrate this drug during pregnancy and lactation period.  [Pediatric administration] There has been no enough clinical experience on the application on children. [Elderly people] Clinical studies have not observed a significant difference of the security and efficacy between the elderly population and young population. But it can’t be exclude that the sensitivity of some elderly patients can be increased.
Contraindications	1. It should be contraindicated in patients known to be allergic to duloxetine or any of the inactive ingredients contained in the product.  2. It should be prohibited to apply it in combination with monoamine oxidase inhibitors (MAOIs). It is also not allowed to administrate this drug within 14 days after the withdrawal of MAOIs; According to the half-life of duloxetine, only after the five days of the withdrawal of duloxetine can the patients begin to administrate MAOIs. 3. Clinical trials have shown that duloxetine can increase the risk of mydriasis and therefore the angle-closure glaucoma patients without control should avoid applying duloxetine.
Chemical Properties	White Crystalline Solid
Usage	Labelled Duloxetine, which is used as an antidepressant. A dual serotonin and norepinephrine reuptake inhibitor (SNRI). Current lot is 97% d7 with no d0, d1 or d2
Usage	An antidepressant. A dual serotonin and norepinephrine reuptake inhibitor (SNRI). Used in treatment of stress urinary incontinence.
Usage	leucotriene antagonist, antiasthmatic
Usage	anti-depressant, analgesic for osteoarthiritis and musculoskeletal pain
Usage	solubility H2O: soluble5 mg/mL (clear solution, warmed)