Enantioselective analysis of venlafaxine and its active metabolites: A review on the separation methodologies

Félix

Enviro Toxic and Chemistry

et al. 2022

Venlafaxine is a chiral antidepressant detected in aquatic compartments. It was recently included in the 3rd Watch List from the European Union. The present study aimed to investigate venlafaxine toxicity effects, targeting possible enantioselective effects, using two aquatic organisms, daphnia (Daphnia magna) and zebrafish (Danio rerio). Specimens were exposed to both racemate, (R,S)‐venlafaxine (VEN), and to pure enantiomers. Acute assays with daphnia showed that up to 50 000 μg/L of the (R,S)‐VEN induced no toxicity. Organisms were also exposed to sublethal concentrations (25–400 μg/L) of (R,S)‐, (R)‐ and (S)‐VEN, for 21 days. No significant effects on mortality, age at first reproduction, and size of the first clutch were observed. However, a decrease in fecundity was observed for both enantiomers at the highest concentration. Regarding zebrafish, the effects of venlafaxine on mortality, embryo development, behavior, biochemistry, and melanin pigmentation were investigated after 96 h of exposure to the range of 0.3–3000 μg/L. (R)‐VEN significantly increased the percentage of malformations in comparison with (S)‐VEN. Behavior was also enantiomer dependent, with a decrease in the total distance moved and an increase in avoidance behavior observed in organisms exposed to (R)‐VEN. Despite the biochemical variations, no changes in redox homeostasis were observed. (R)‐VEN also led to an increase in zebrafish pigmentation. The different susceptibility to venlafaxine and enantioselective effects were observed in zebrafish. Our results suggest that at environmental levels (R,S)‐VEN and pure enantiomers are not expected to induce harmful effects in both organisms, but (R)‐VEN increased malformations in zebrafish larvae, even at reported environmental levels. These results highlight the importance of including enantioselective studies for an accurate risk assessment of chiral pollutants. Environ Toxicol Chem 2022;41:1851–1864. © 2022 SETAC

Section: Introductionmentioning

confidence: 99%

Enantioselective Ecotoxicity of Venlafaxine in Aquatic Organisms: Daphnia and Zebrafish

Félix

Enviro Toxic and Chemistry

et al. 2022

“…Another well-studied example concerning enantioselectivity in both the main compound and its metabolites is venlafaxine. Venlafaxine ( Figure 5 ) is a serotonin and norepinephrine reuptake inhibitor marketed in racemic form as an antidepressant agent [ 44 ]. However, despite the fact that venlafaxine is marketed as a racemate, the enantiomers show differences in their activity, with the ( R )-enantiomer inhibiting the synaptic reuptake of norepinephrine and serotonin, while ( S )-enantiomer inhibits only the serotonin.…”

Section: Enantioselectivity In Drug Pharmacokineticsmentioning

confidence: 99%

“…CYP2D6 catalyzes the biotransformation of both the enantiomers into N , O -didesmethylvenlafaxine, although there is greater stereoselectivity for the ( R )-venlafaxine enantiomer. However, partial metabolic clearance of both enantiomers in N -desmethylvenlafaxine, mediated by the enzyme CYP3A4, is not stereoselective [ 44 ]. Polymorphisms and drug interactions may occur due to CYP2D6 and, to some extent, CYP2C19, which have been shown to significantly influence the pharmacokinetics and metabolic clearance of venlafaxine and the formation of its active metabolite, O -desmethylvenlafaxine [ 45 ].…”

Section: Enantioselectivity In Drug Pharmacokineticsmentioning

confidence: 99%

“…It was concluded that although the use of local anesthetics in an enantiomerically pure form has advantageous properties in terms of its activity and lowtoxicity, its potential has not yet been fully studied and verified [ 6 ]. The enantioselective methods to study pharmacokinetics and pharmaceutical formulations of venlafaxine were also recently revised, which encompass LC-UV, LC-MS, LC-MS/MS, and capillary electrophoresis methods [ 44 ]. Many case studies were reported in this review, such as a study on healthy Chinese volunteers, in whom, after the administration of venlafaxine, ( S )-venlafaxine concentrations were approximately twice as high as those of ( R )-venlafaxine, strongly suggesting a stereoselective disposition [ 103 ].…”

Section: Chiral Analysis In Pharmacokineticsmentioning

confidence: 99%

See 1 more Smart Citation

Enantioselectivity in Drug Pharmacokinetics and Toxicity: Pharmacological Relevance and Analytical Methods

et al. 2021

Enzymes, receptors, and other binding molecules in biological processes can recognize enantiomers as different molecular entities, due to their different dissociation constants, leading to diverse responses in biological processes. Enantioselectivity can be observed in drugs pharmacodynamics and in pharmacokinetic (absorption, distribution, metabolism, and excretion), especially in metabolic profile and in toxicity mechanisms. The stereoisomers of a drug can undergo to different metabolic pathways due to different enzyme systems, resulting in different types and/or number of metabolites. The configuration of enantiomers can cause unexpected effects, related to changes as unidirectional or bidirectional inversion that can occur during pharmacokinetic processes. The choice of models for pharmacokinetic studies as well as the subsequent data interpretation must also be aware of genetic factors (such as polymorphic metabolic enzymes), sex, patient age, hepatic diseases, and drug interactions. Therefore, the pharmacokinetics and toxicity of a racemate or an enantiomerically pure drug are not equal and need to be studied. Enantioselective analytical methods are crucial to monitor pharmacokinetic events and for acquisition of accurate data to better understand the role of the stereochemistry in pharmacokinetics and toxicity. The complexity of merging the best enantioseparation conditions with the selected sample matrix and the intended goal of the analysis is a challenge task. The data gathered in this review intend to reinforce the importance of the enantioselectivity in pharmacokinetic processes and reunite innovative enantioselective analytical methods applied in pharmacokinetic studies. An assorted variety of methods are herein briefly discussed.

Biomedical Chromatography

“…Some old or recent reviews dealing with the literature reporting contributions to the derivatization for HPLC with specified detections (Higashi & Ogawa, 2016;Santa, 2011Santa, , 2013 may complete the present review. Reviews dedicated to the bioanalytical methods including derivatization for certain compounds are also available in the recent literature (Batra & Bhushan, 2018a, 2018bHancu, Lupu, Milan, Budau, & Barabas-Hajdu, 2020;Jia & Bartlett, 2020;Knikman, Rosing, Guchelaar, Cats, & Beijnen, 2020;Suresh, Trivedi, Srinivas, & Mullangi, 2020). Apecial attention was given to the bioanalysis of anticancer drugs, to which a very recent review has been dedicated that includes HPLC methods based on chemical derivatization (Sabourian et al, 2020).…”

mentioning

confidence: 99%

Derivatization procedures and their analytical performances for HPLC determination in bioanalysis

David

Moldoveanu

Galaon

2020

Derivatization, or chemical structure modification, is often used in bioanalysis performed by liquid chromatography technique in order to enhance detectability or to improve the chromatographic performance for the target analytes. The derivatization process is discussed according to the analytical procedure used to achieve the reaction between the reagent and the target compounds (containing hydroxyl, thiol, amino, carbonyl and carboxyl as the main functional groups involved in derivatization). Important procedures for derivatization used in bioanalysis are in situ or based on extraction processes (liquid-liquid, solid-phase and related techniques) applied to the biomatrix. In the review, chiral, isotope-labeling, hydrophobicity-tailored and post-column derivatizations are also included, based on representative publications in the literature during the last two decades. Examples of derivatization reagents and brief reaction conditions are included, together with some bioanalytical applications and performances (chromatographic conditions, detection limit, stability and sample biomatrix).