Achiral and chiral analysis of duloxetine by chromatographic and electrophoretic methods, a review on the separation methodologies

Lupu, Daniela; Hancu, Gabriel

doi:10.1002/bmc.4883

Cited by 3 publications

(1 citation statement)

References 41 publications

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“…It has a chiral center and is applied as a single enantiomer in medication, namely, as ( S )-duloxetine. Both the enantiomeric forms of duloxetine effectively inhibit norepinephrine and serotonin reuptake, although the ( S )-form is 2-fold more active than the ( R )-form and is sold as a single-enantiomeric form for clinical therapy [ 65 , 66 ]. Studies on the binding of duloxetine enantiomers to human serum albumin indicate that the binding constant for the ( R )-enantiomer is greater than that for rac-duloxetine.…”

Section: Serotonin–norepinephrine Reuptake Inhibitorsmentioning

confidence: 99%

Chirality of antidepressive drugs: an overview of stereoselectivity

et al. 2022

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Stereochemistry plays an important role in drug design because the enantiomers of a drug frequently vary in their biological action and pharmacokinetic profiles. Racemates of a drug with either an inactive or an unsafe enantiomer can lead to detrimental effects. The manufacturing industry may still produce racemates, but such decisions must pass through rigorous analyses of the pharmacological and pharmacokinetic characteristics of the particular enantiomer related to the racemates. The pharmacokinetics of antidepressants or antidepressive agents is stereoselective and predominantly favors one enantiomer. The use of pure enantiomers offers (i) better specificity than the racemates in terms of certain pharmacological actions, (ii) enhanced clinical indications, and (iii) optimized pharmacokinetics. Therefore, controlling the stereoselectivity in the pharmacokinetics of antidepressive drugs is of critical importance in dealing with depression and psychiatric conditions. The objective of this review is to highlight the importance of the stereochemistry of antidepressants in the context of the design and development of new chirally pure pharmaceuticals, the potential complications caused by using racemates, and the benefits of using pure enantiomers.

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Section: Serotonin–norepinephrine Reuptake Inhibitorsmentioning

confidence: 99%

Chirality of antidepressive drugs: an overview of stereoselectivity

et al. 2022

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Capillary electrophoresis methods for impurity profiling of drugs: A review of the past decade

Shah

Patel

Nagja

et al. 2022

Journal of Pharmaceutical Analysis

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In vitro, in vivo, and in silico approaches for evaluating the preclinical DMPK profiles of ammoxetine, a novel chiral serotonin and norepinephrine reuptake inhibitor

Zhu,

Li,

Luo

et al. 2024

Front. Pharmacol.

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Background and AimAmmoxetine, a novel chiral serotonin and norepinephrine reuptake inhibitor, holds promise for major depressive disorder treatment. This study aimed to thoroughly investigate its preclinical drug metabolism and pharmacokinetics (DMPK) profiles.MethodsThe preclinical DMPK profiles of ammoxetine were examined through in vitro, in vivo, and in silico methods.ResultsAssessment of blood-brain barrier penetration via MDCK-MDR1 cells revealed strong brain permeation by ammoxetine, despite being a probable P-glycoprotein (P-gp) substrate. Molecular docking indicated a robust binding interaction between ammoxetine and P-gp. Ammoxetine was well absorbed orally, with Tmax ranging from 0.75 to 3.83 h in rats and 0.75–1.40 h in beagle dogs. At a 2 mg/kg dose in beagle dogs, ammoxetine exhibited an absolute bioavailability of approximately 42%. Plasma protein binding rates were around 50%–60% in beagle dogs, rats, and humans, suggesting moderate binding. Tissue distribution studies displayed rapid and extensive ammoxetine spread in major rat tissues post-gavage, with notable brain exposure and no tissue accumulation. Cumulative excretion rates in rats’ urine, feces, and bile accounted for only 1.11% of the total administered drug, indicating extensive transformation into metabolites. Chiral inversion of ammoxetine was absent in vivo. Metabolic stability varied across species using liver microsomes, but beagle dogs showed clearance rates more akin to humans. Metabolic pathways unveiled two key metabolites, M1 and M2. M1, likely generated through methylenedioxyphenyl ring oxidation, involves CYP2C19 and CYP3A4, crucial human cytochrome P450 (CYP) enzymes for liver metabolism, while M2 is M1’s glucuronide conjugate. Ammoxetine may exhibit saturation elimination trends with increasing doses in rats and beagle dogs. A high-throughput assay using the cocktail-substrate method indicated weak CYP inhibition by ammoxetine on CYP2D6 and CYP1A2, with minimal effects on other CYP enzymes, suggesting a low likelihood of CYP inhibition-related drug-drug interactions.ConclusionThis study presents encouraging DMPK profiles of ammoxetine, backing its potential as a candidate compound for future clinical assessments.

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Achiral and chiral analysis of duloxetine by chromatographic and electrophoretic methods, a review on the separation methodologies

Cited by 3 publications

References 41 publications

Chirality of antidepressive drugs: an overview of stereoselectivity

Chirality of antidepressive drugs: an overview of stereoselectivity

Capillary electrophoresis methods for impurity profiling of drugs: A review of the past decade

In vitro, in vivo, and in silico approaches for evaluating the preclinical DMPK profiles of ammoxetine, a novel chiral serotonin and norepinephrine reuptake inhibitor

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