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Individual Enantiomers (individual + enantiomer)

Distribution by Scientific Domains

Medical Sciences	50%
Chemistry	30%

Selected Abstracts

Perspectives on ecological risk assessment of chiral compounds

INTEGRATED ENVIRONMENTAL ASSESSMENT AND MANAGEMENT, Issue 3 2009
Jacob K Stanley
Abstract Enantiomers of chiral contaminants can significantly differ in environmental fate as well as in effects. Despite this fact, such differences are often ignored in regulation and in practice, injecting uncertainty into the estimation of risk of chiral compounds. We review the unique challenges posed by stereochemistry to the ecological risk assessment of chiral contaminants and existing regulatory guidance for chiral pharmaceuticals and pesticides in the United States. We identify the advantages of obtaining data on fate and effects of each individual enantiomer of chiral contaminants that are either distributed as or may end up as enantiomer mixtures in the environment due to enantiomerization. Because enantiomers of the same compound are highly likely to coexist in the environment with each other and can result in nonadditive effects, we recommend treatment of enantiomers as components of a mixture using widely accepted mixture models from achiral risk assessment. We further propose the enantiomer hazard ratio for retrospectively characterizing relative enantiomer risk and examine uncertainty factor magnitudes for effects analysis. [source]

Determination of the 2,3-pentadienedioic acid enantiomer interconversion energy barrier 1.

JOURNAL OF SEPARATION SCIENCE, JSS, Issue 15 2006
Classical kinetic approach
Abstract A classical kinetic method was used to determine the energy barrier for the interconversion of 2,3-pentadienedioic acid enantiomers. Each individual enantiomer was isolated by collecting the appropriate peaks from the HPLC enantiomeric separation, of racemic 2,3-pentadienedioic acid. The isolated enantiomers were racemized at 22°C using various interconversion times. The ratio of enantiomers in each reaction solution was determined by HPLC at 22°C. The corresponding peak areas of the enantiomers and the interconversion times obtained from the HPLC chromatograms were used to calculate both the interconversion rate constants describing (+) , (,) and (,) , (+) interconversions as well as the energy barriers. It was confirmed that the interconversion of 2,3-pentadienedioic acid enantiomers is a first-order kinetic reaction. Both semiempirical and ab initio methods were used to explore the mechanism of the interconversion of 2,3-pentadienedioic acid enantiomers, and to calculate the interconversion energy barrier. Comparison of the interconversion energy barriers found by the ab initio method (,G# = 110.7 kJ/mol) and by classical kinetics in the mobile phase solution at 22°C (,Gapp = 93.9 ± 0.2 kJ/mol) shows a difference which may be attributed to the different conditions assumed in the theoretical calculation (i. e., a gaseous state) and the actual experimental conditions (i. e., liquid solution) and a possible catalytic effect of the solution composition. [source]

The pharmacokinetics of ethosuximide enantiomers in the rat

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2001
J. Mifsud
Abstract A chiral gas chromatographic assay previously developed for quantitative analysis of ethosuximide and its major metabolites in rat urine has been adapted for the analysis of the drug in plasma. Ethosuximide, both as a racemic mixture and as the individual enantiomers, was administered to conscious rats by the intravenous (i.v.) and intraperitoneal (i.p.) routes. Pharmacokinetic parameters were estimated using standard non-compartmental methods. Comparison of the pharmacokinetic parameters of (S)-ethosuximide and (R)-ethosuximide showed that total body clearance of (R)-ethosuximide was significantly larger than that of (S)-ethosuximide and that elimination half-life was significantly shorter following administration of both 40 mg i.v. and i.p. doses, indicating that there is stereoselective elimination of ethosuximide. However, no significant differences were found between apparent volumes of distribution. In addition, no significant differences were found for either enantiomer between the estimates of the pharmacokinetic parameters obtained following administration as the individual enantiomer and as a constituent of the racemic mixture. This indicates that, at the doses studied, the preferential faster elimination of (R)-ethosuximide is not dependent upon the presence of the (S)-enantiomer. Also, for each enantiomer, the lack of any significant difference between estimates of clearance when administered as part of a racemic mixture and when administered separately indicates that neither enantiomer affects the clearance of the other. Copyright © 2001 John Wiley & Sons, Ltd. [source]

Separation and aquatic toxicity of enantiomers of the pyrethroid insecticide lambda-cyhalothrin,

ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 1 2008
Chao Xu
Abstract Chiral pollutants are receiving growing environmental concern due to differential biological activities of their enantio-mers. In the present study, enantiomeric separation of the pyrethroid insecticide lambda-cyhalothrin (LCT) was investigated by high-performance liquid chromatography (HPLC) using the columns of Chiralpak AD (amylase tris[3,5-dimethyl-phenylcarbamate]), Chiralpak AS (amylase tris[(S)-1-phenyl carbamate]), Chiralcel OD (cellulose tris[3,5-dimethylphenyl carbamate]), and Chiralcel OJ (cellulose tris[4-methyl benzoate]) with different chiral stationary phases. The differential toxicities of the enantiomers in aquatic systems were evaluated using the acute zebrafish (Danio rerio) toxicity test and the zebrafish embryo test. The enantiomers of LCT were separated completely on all the columns tested and detected by circular dichroism at 236 nm. Better separations were achieved at lower temperatures (e.g., 20°C) and lower levels of polar modifiers (,5%) in mobile phase. Ethanol was found to be a good modifier of the mobile phase for all the columns, although isopropanol acted better for the Chiralcel OD column. The (,)-enantiomer was >162 times more toxic than its antipode to zebrafish in the acute test. The embryo test indicated that the exposure to LCT enantioselectively induced crooked body, yolk sac edema, and pericardial edema and that the (,)-enantiomer was 7.2 times stronger than the (+)-enantiomer in 96-h mortality. The malformations were induced by the racemate and its (,)-enantiomer at lower concentrations tested (e.g., 50 ,g L,1), whereas the (+)-enantiomer induced malformations at relatively higher concentrations (,100 ,g L,1). These results suggest that the toxicological effects of chiral pesticides must be evaluated using their individual enantiomers. [source]

Pharmacokinetics of Levetiracetam and Its Enantiomer (R)-,-ethyl-2-oxo-pyrrolidine acetamide in Dogs

EPILEPSIA, Issue 7 2001
Nina Isoherranen
Summary: ,Purpose: The new antiepileptic drug, levetiracetam (LEV, ucb LO59), is a chiral molecule with one asymmetric carbon atom whose anticonvulsant activity is highly enantioselective. The purpose of this study was to evaluate and compare the pharmacokinetics (PK) of LEV [(S)-,-ethyl-2-oxo-pyrrolidine acetamide] and its enantiomer (R)-,-ethyl-2-oxo-pyrrolidine acetamide (REV) after i.v. administration to dogs. This is the first time that the pharmacokinetics of both enantiomers has been evaluated. Methods: Optically pure LEV and REV were synthesized, and 20 mg/kg of individual enantiomers was administered intravenously to six dogs. Plasma and urine samples were collected until 24 h, and the concentrations of LEV and REV were determined by an enantioselective assay. The levels of 2-pyrrolidone- N -butyric acid, an acid metabolite of LEV and REV, were determined by high-performance liquid chromatography (HPLC). The data were used for PK analysis of LEV and REV. Results: LEV and REV had similar mean ± SD values for clearance; 1.5 ± 0.3 ml/min/kg and volume of distribution; 0.5 ± 0.1 L/kg. The half-life (t1/2) and mean residence time (MRT) of REV (t1/2, 4.3 ± 0.8 h, and MRT, 6.0 ± 1.1 h) were, however, significantly longer than those of LEV (t1/2, 3.6 ± 0.8 h, and MRT, 5.0 ± 1.2 h). The renal clearance and fraction excreted unchanged for LEV and REV were significantly different. Conclusions: In addition to the enantioselective pharmacodynamics, ,-ethyl-2-oxo-pyrrolidine acetamide has enantioselective PK. The enantioselectivity was observed in renal clearance. Because REV has more favorable PK in dogs than LEV, the higher antiepileptic potency of LEV is more likely due to intrinsic pharmacodynamic activity rather than to enantioselective PK. [source]

Development and validation of a stereoselective HPLC method for the determination of the in vitro transport of nateglinide enantiomers in rat intestine

JOURNAL OF SEPARATION SCIENCE, JSS, Issue 12 2007
Srinivas Maddi
Abstract A simple stereoselective high performance liquid chromatographic method was developed for the determination of the in vitro transport of the enantiomers of nateglinide (N -(trans -4-isopropylcyclohexyl-carbonyl)-phenylalanine) in the rat intestine using a Chiralcel OJ-RH column (150×4.0 mm, 5 ,m). The effects of the mobile phase composition, pH, the flow rate, and the temperature on the chromatographic separation were investigated. The enantioseparation was achieved at 33°C using a mobile phase containing 100 mM potassium dihydrogen phosphate, pH 2.5, and ACN (32:68 v/v) delivered at a flow rate of 1 mL/min. The analytes were monitored at 210 nm and linearity (r >0.99) was obtained for a concentration range of 0.5,50 ,g/mL. The LOD and LOQ were 0.2 and 0.5 ,g/mL for the R -enantiomer and 0.2 and 0.8 ,g/mL for the S -enantiomer, respectively. Both, the intra- and interday accuracy and precision of the calibration curves were determined. The method was successfully applied to estimate the in vitro passage of the enantiomers and the racemate of nateglinide in duodenum, jejunum, and ileum of rats. Generally, higher concentrations of nateglinide and the S -enantiomer were observed when the racemate was administered compared to administration of the individual enantiomers of nateglinide. [source]

A comparative proteomic analysis of HepG2 cells incubated by S(,) and R(+) enantiomers of anti-coagulating drug warfarin

PROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 7 2010
Jing Bai
Abstract Warfarin is a commonly prescribed oral anti-coagulant with narrow therapeutic index. It interferes with vitamin K cycle to achieve anti-coagulating effects. Warfarin has two enantiomers, S(,) and R(+) and undergoes stereoselective metabolism, with the S(,) enantiomer being more effective. We reported that the intracellular protein profile in HepG2 cells incubated with S(,) and R(+) warfarin, using iTRAQ-coupled 2-D LC-MS/MS. In samples incubated with S(,) and R(+) warfarin alone, the multi-task protein Protein SET showed significant elevation in cells incubated with S(,) warfarin but not in those incubated with R(+) warfarin. In cells incubated with individual enantiomers of warfarin in the presence of vitamin K, protein disulfide isomerase A3 which is known as a glucose-regulated protein, in cells incubated with S(,) warfarin was found to be down-regulated compared to those incubated with R(+) warfarin. In addition, Protein DJ-1 and 14-3-3 Protein, were down-regulated in cells incubated with either S(,) or R(+) warfarin regardless of the presence of vitamin K. Our results indicated that Protein DJ-1 may act as an enzyme for expression of essential enzymes in vitamin K cycle. Taken together, our findings provided molecular evidence on a comprehensive protein profile on warfarin,cell interaction, which may shed new lights on future improvement of warfarin therapy. [source]

The pharmacokinetics of ethosuximide enantiomers in the rat

Stereoselective pharmacokinetics of cisapride in healthy volunteers and the effect of repeated administration of grapefruit juice

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2001
Zeruesenay Desta
Aims, To determine whether the pharmacokinetics of cisapride and its interaction with grapefruit juice are stereoselective. Methods, The study was a randomized, two-phase cross over design with a washout period of 2 weeks. Ten healthy volunteers were pretreated with either water or 200 ml double strength grapefruit juice three times a day for 2 days. On the 3rd each subject ingested a single 10 mg dose of rac -cisapride tablet. Double strength grapefruit juice (200 ml) or water was administered during cisapride dosing and 0.5 and 1.5 h thereafter. Blood samples were collected before and for 32 h after cisapride administration. Plasma concentrations of cisapride enantiomers were measured by a chiral h.p.l.c. method. A standard 12-lead ECG was recorded before cisapride administration (baseline) and 2, 5, 8, and 12 h later. Results, This study showed that cisapride pharmacokinetics are stereoselective. In control (water treated) subjects, the mean Cmax (30 ± 13.6 ng ml,1; P = 0.0008) and AUC(0, ,) (201 ± 161 ng ml,1 h; P = 0.029) of (,)-cisapride were significantly higher than the Cmax (10.5 ± 3.4 ng ml,1) and AUC(0, ,) (70 ± 51.5 ng ml,1 h) of (+)-cisapride. There was no marked difference in elimination half-life between (,)-cisapride (4.7 ± 2.7 h) and (+)-cisapride (4.8 ± 3 h). Compared with the water treated group, grapefruit juice significantly increased the mean Cmax of (,)-cisapride from 30 ± 13.6,55.5 ± 18 ng ml,1 (95% CI on mean difference, ,33, ,17; P = 0.00005) and of (+)-cisapride from 10.5 ± 3.4 to 18.4 ± 6.2 ng ml,1 (95% CI on mean difference, ,11.8, ,3.9, P = 0.00015). The mean AUC(0, ,) of (,)-cisapride was increased from 201 ± 161 to 521.6 ± 303 ng ml,1 h (95% CI on mean difference, ,439, ,202; P = 0.0002) and that of (+)-cisapride from 70 ± 51.5 to 170 ± 91 ng ml,1 h (95% CI on mean difference, ,143, ,53; P = 0.0005). The tmax was also significantly increased for both enantiomers (from 1.35 to 2.8 h for (,)-cisapride and from 1.75 to 2.9 h for (+)-cisapride in the control and grapefruit juice group, respectively; P < 0.05). The t½ of (,)-cisapride was significantly increased by grapefruit juice, while this change did not reach significant level for (+)-cisapride. The proportion of pharmacokinetic changes brought about by grapefruit juice was similar for both enantiomers, suggesting non-stereoselective interaction. We found no significant difference in mean QTc intervals between the water and grapefruit juice treated groups. Conclusions, The pharmacokinetics of cisapride is stereoselective. Grapefruit juice elevates plasma concentrations of both (,)- and (+)-cisapride, probably through inhibition of CYP3A in the intestine. At present, there are no data on whether the enantiomers exhibit stereoselective pharmacodynamic actions. If they do, determination of plasma concentrations of the individual enantiomers as opposed to those of racemic cisapride may better predict the degree of drug interaction, cardiac safety and prokinetic efficacy of cisapride. [source]

Characterization of the anticonvulsant profile and enantioselective pharmacokinetics of the chiral valproylamide propylisopropyl acetamide in rodents

BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2003
Nina Isoherranen
Propylisopropyl acetamide (PID) is a new chiral amide derivative of valproic acid. The purpose of this study was to evaluate the anticonvulsant activity of PID in rodent models of partial, secondarily generalized and sound-induced generalized seizures which focus on different methods of seizure induction, both acute stimuli, and following short-term plastic changes as a result of kindling, and to assess enantioselectivity and enantiomer,enantiomer interactions in the pharmacokinetics and pharmacodynamics of racemic PID and its pure enantiomers in rodents. Anticonvulsant activity of (S)-PID, (R)-PID and racemic PID was evaluated in the 6 Hz psychomotor seizure model in mice, in the hippocampal kindled rat, and in the Frings audiogenic seizure susceptible mouse. The pharmacokinetics of (S)-PID and (R)-PID was studied in mice and rats. In mice (S)-PID, (R)-PID and racemic PID were effective in preventing the 6 Hz seizures with (R)-PID being significantly (P<0.05) more potent (ED50 values 11 mg kg,1, 46 mg kg,1 and 57 mg kg,1 at stimulation intensities of 22, 32 and 44 mA, respectively) than (S)-PID (ED50 values 20 mg kg,1, 73 mg kg,1 and 81 mg kg,1 at stimulation intensities of 22, 32 and 44 mA, respectively). (S)-PID, (R)-PID and racemic PID also blocked generalized seizures in the Frings mice (ED50 values 16 mg kg,1, 20 mg kg,1 and 19 mg kg,1 respectively). In the hippocampal kindled rat a dose of 40 mg kg,1 of (R)- and (S)-PID prevented the secondarily generalized seizure, whereas racemic PID also blocked the expression of partial seizures following an i.p. dose of 40 mg kg,1. Racemic PID also significantly increased the seizure threshold in this model. Mechanistic studies showed that PID did not affect voltage-sensitive sodium channels or kainate-, GABA- or NMDA- evoked currents. The pharmacokinetics of PID was enantioselective following i.p. administration of individual enantiomers to mice, with (R)-PID having lower clearance and longer half-life than (S)-PID. In rats and mice, no enantioselectivity in the pharmacokinetics of PID was observed following administration of the racemate, which may be due to enantiomer,enantiomer interaction. This study demonstrated that PID has both enantioselective pharmacokinetics and pharmacodynamics. The better anticonvulsant potency of (R)-PID in comparison to (S)-PID may be due to its more favorable pharmacokinetic profile. The enhanced efficacy of the racemate over the individual enantiomers in the kindled rat may be explained by a pharmacokinetic enantiomer,enantiomer interaction in rats. This study also showed the importance of studying the pharmacokinetics and pharmacodynamics of chiral drugs following administration of the individual enantiomers as well as the racemic mixture. British Journal of Pharmacology (2003) 138, 602,613. doi:10.1038/sj.bjp.0705076 [source]