Enantioselective Toxic Effects and Degradation of Myclobutanil Enantiomers in Scenedesmus obliquus

Research on the enantioselective environmental behavior of chiral pesticides has been a hot spot of environmental chemistry recently. In this study, the acute toxicity of myclobutanil enantiomers was investigated with the aquatic algae Scendesmus obliquus. After exposure for 96 h, the EC₅₀ values for (?)‐myclobutanil, rac‐myclobutanil and (+)‐myclobutanil were 3.951, 2.760, and 2.128 mg/L, respectively. The photosynthetic pigment (chlorophyll a, chlorophyll b, and carotenoids) and antioxidant enzyme activities catalase (CAT) were determined to evaluate the different toxic effects when S. obliquus were exposed to 1.5, 5 and 15 mg/L of rac‐myclobutanil, (?)‐myclobutanil, and (+)‐myclobutanil for 96 h, respectively. In addition, the degradation of myclobutanil enantiomers in S. obliquus was also studied. Myclobutanil in the medium inoculated with algae degraded faster than in the uninoculated medium. The degradation of (?)‐myclobutanil was faster than that of (+)‐myclobutanil at a concentration of 3 mg/L. On the basis of these data, the acute toxicity and toxic effects of myclobutanil against S. obliquus were concluded to be enantioselective, and such enantiomeric differences should be taken into consideration in pesticide risk assessment. Chirality 25:858–864, 2013. © 2013 Wiley Periodicals, Inc.     

Studies of Enantiomeric Degradation of the Triazole Fungicide Hexaconazole in Tomato,Cucumber, and Field Soil by Chiral Liquid Chromatography–Tandem Mass Spectrometry

Chiral pesticide enantiomers often show different bioactivity and toxicity; however, this property is usually ignored when evaluating their environmental and public health risks. Hexaconazole is a chiral fungicide used on a variety of crops for the control of many fungal diseases. This use provides opportunities for the pollution of food and soil. In this study, a sensitive and convenient chiral liquid chromatography coupled with tandem mass spectrometry (LC‐MS/MS) method was developed and validated for measuring hexaconazole enantiomers in tomato, cucumber, and soil. Separation was by a reversed‐phase Chiralcel OD‐RH column, under isocratic conditions using a mixture of acetonitrile‐2 mM ammonium acetate in water (60/40, v/v) as the mobile phase at a flow rate of 0.4 mL/min. Parameters including the matrix effect, linearity, precision, accuracy and stability were undertaken. Then the proposed method was successfully applied to investigate the possible enantioselective degradation of rac‐hexaconazole in plants (tomato and cucumber) and soil under field conditions. The degradation of the two enantiomers of hexaconazole proved to be enantioselective and dependent on the media: The (+)‐enantiomer showed a faster degradation in plants, while the (?)‐enantiomer dissipated faster than the (+)‐form in field soil, resulting in relative enrichment of the opposite enantiomer. The results of this work demonstrate that both the environmental media and environmental conditions influenced the direction and rate of enantioselective degradation of hexaconazole. Chirality 25:160–169, 2013. © 2013 Wiley Periodicals, Inc.     

Gender‐Related In Vitro Metabolism of Hexaconazole and Its Enantiomers in Rats

In the present study we investigated the enantioselective disappearance of hexaconazole in rat liver microsomes system prepared from both genders. High‐performance liquid chromatography (HPLC) was used for identification and quantification. The degradation of the (+)‐hexaconazole was faster than that of the (?)‐hexaconazole in racemic hexaconazole and single enantiomer incubation in both sexes. The degradation half‐life of the (+)‐hexaconazole or (?)‐hexaconazole was also gender‐related. The metabolism of (+)‐hexaconazole and (?)‐hexaconazole were faster in male rat hepatic microsomes than that in female, suggesting that at least one of the cytochrome P450s (CYP) in the male rat liver microsomes system responsible for hexaconazole metabolism was male‐specific or considerably more active. Kinetic assays showed that the intrinsic clearance in male rat liver microsomes was higher than that in female. All these results strongly suggest that sexual dimorphic metabolism of hexaconazole exists in rats. The inhibition experiments with CYP inhibitors showed that the inhibitory effect of inhibitors was enantioselective and affected by sex. The results suggest that the enantioselective metabolism of hexaconazole was determined by the amount of hepatic cytochrome P450 and the expression of individual isoforms of CYPs. Chirality 25:852–857, 2013. © 2013 Wiley Periodicals, Inc.     

Separation and toxicity of salithion enantiomers

Enantioseletive toxicities of chiral pesticides have become an environmental concern recently. In this study, we evaluated the enantiomeric separation of salithion on a suite of commercial chiral columns and assessed the toxicity of enantiomers toward butyrylcholinesterase and Daphnia magna. Satisfactory separations of salithion enantiomers could be achieved on all tested columns, that is, Chiralcel OD, Chiralcel OJ, and Chiralpak AD column. However, the Chiralpak AD column offered the best separation and was chosen to prepare micro‐scale of pure salithion enantiomers for subsequent bioassays. The first and second enantiomers eluted on the Chiralpak AD column were further confirmed to be (?)‐S‐salithion and (+)‐R‐salithion, respectively. The half inhibition concentrations to butyrylcholinesterase of racemate, (+)‐R‐salithion, and (?)‐S‐salithion were 33.09, 2.92, and 15.60 mg/l, respectively, showing (+)‐R‐enantiomer being about 5.0 times more potent than its (?)‐S‐form. However, the median lethal concentrations (96 h) of racemate, (+)‐R‐salithion, and (?)‐S‐salithion toward D. magna were 3.54, 1.10, and 0.36 μg/l, respectively, suggesting that (?)‐S‐salithion was about 3.0 times more toxic than (+)‐R‐form. Racemic salithion was less toxic than either of the enantiomers in both bioassays, suggesting that antagonistic interactions might occur between the enantiomers during the toxication action. This work reveals that the toxicity of salithion toward butyrylcholinesterase and D. magna is enantioselective, and this factor should be taken into consideration in the environmental risk assessment of salithion. Chirality 2009. © 2009 Wiley‐Liss, Inc.     

Enantioselective toxicological response of the green alga Scenedesmus obliquus to isocarbophos

Chiral compounds usually behave enantioselectively in phyto‐biochemical processes. Isocarbophos (ICP) is a chiral pesticide that is widely used. To evaluate the toxicological response of ICP and its enantiomers to Scenedesmus obliquus, algal growth, total chlorophyll, total soluble protein, and the superoxide anion radicals (O₂^?‐) were investigated. The microalgae were treated with ICP and its enantiomers at 0.01–10 mg/l for 96 h. The growth of S. obliquus was stimulated at low levels of ICP and its enantiomers (0.01–1 mg/l), but all were inhibited at high concentrations (10 mg/l). The total soluble protein content and total chlorophyll content of the tested green alga S. obliquus gradually increased, depending on the growth of algal cells in the medium. Meanwhile, the content of O₂^?‐ was decreased. Interestingly, the cell number and content of the chlorophylls and protein decreased with increasing levels of concentration, whereas O₂^?‐ increased. Our results indicated that enantioselectivity was observed in the dose–response of ICP and its enantiomers in S. obliquus. The high O₂^?‐ level might lead to the death of S. obliquus. The stimulation of growth suggests a regulatory mechanism that is related to the capability of the algae to adapt to the O₂^?‐. Chirality 24:481–485, 2012. © 2012 Wiley Periodicals, Inc.     

The biological activities of prothioconazole enantiomers and their toxicity assessment on aquatic organisms

Chiral fungicide prothioconazole has a wide range of antifungal spectrum; however, little research has been conducted to evaluate prothioconazole on an enantiomeric level. Five target pathogens and three common aquatic organisms were tested for the enantioselective bioactivity and toxicity of prothioconazole in this work. The antifungal activity of the enantiomers against wheat phytoalexin, rice blast fungus, exserohilum turcicum, Alternaria triticina, and Fusarium avenaceum was determined, and it was found that (?)‐prothioconazole were 85 to 2768 times more active than (+)‐prothioconazole toward these target organisms. In order to reflect the risk to aquatic ecosystem, the acute toxicity of the enantiomers to Daphnia magna, Chlorella pyrenoidosa, and Lemna minor L. was assessed. It was observed that the toxicity of (?)‐prothioconazole to D. magna was 2.2 times higher than (+)‐prothioconazole, but it was lower to C. pyrenoidosa and L. minor L. The toxicities of (+)‐enantiomer and (?)‐enantiomer to D. magna and C. pyrenoidosa were synergy, indicating that the racemate had higher threat to the organisms. It could be concluded that the effects of prothioconazole on target organisms and the acute toxicity to nontarget species were enantioselective with (?)‐enantiomer possessing higher efficiency and lower toxicity. Such enantiomeric differences should be taken into consideration when assessing the performance of prothioconazole.     

Acute Toxicity,Bioactivity, and Enantioselective Behavior with Tissue Distribution in Rabbits of Myclobutanil Enantiomers

The enantioselective bioactivity against pathogens (Cercospora arachidicola, Fulvia fulva, and Phytophthora infestans) and acute toxicity to Daphnia magna of the fungicide myclobutanil enantiomers were studied. The (+)‐enantiomer in an antimicrobial activity test was about 1.79–1.96 times more active than the (–)‐enantiomer. In the toxicity assay, the calculated 24‐h LC₅₀ values of the (–)‐form, rac‐form and (+)‐form were 16.88, 13.17, and 11.91 mg/L, and the 48‐h LC₅₀ values were 10.15, 9.24, and 5.48 mg/L, respectively, showing that (+)‐myclobutanil was more toxic. Meanwhile, the enantioselective metabolism of myclobutanil enantiomers following a single intravenous (i.v.) administration was investigated in rabbits. Total plasma clearance value (CL) of the (+)‐enantiomer was 1.68‐fold higher than its antipode. Significant differences in pharmacokinetics parameters between the two enantiomers indicated that the high bioactive (+)‐enantiomer was preferentially metabolized and eliminated in plasma. Consistent consequences were found in the tissues (liver, brain, heart, kidney, fat, and muscle), resulting in a relative enrichment of the low‐activity (–)‐myclobutanil. These systemic assessments of the stereoisomers of myclobutanil cannot be used only to investigate environmental and biological behavior, but also have human health implications because of the long persistence of triazole fungicide and enantiomeric enrichment in mammals and humans. Chirality 26:784–789, 2014. © 2014 Wiley Periodicals, Inc.     

Enantioseparation of Mandelic Acid Enantiomers With Magnetic Nano‐Sorbent Modified by a Chiral Selector

In this study, R(+)‐α‐methylbenzylamine‐modified magnetic chiral sorbent was synthesized and assessed as a new enantioselective solid phase sorbent for separation of mandelic acid enantiomers from aqueous solutions. The chemical structures and magnetic properties of the new sorbent were characterized by vibrating sample magnetometry, transmission electron microscopy, Fourier transform infrared spectroscopy, and dynamic light scattering. The effects of different variables such as the initial concentration of racemic mandelic acid, dosage of sorbent, and contact time upon sorption characteristics of mandelic acid enantiomers on magnetic chiral sorbent were investigated. The sorption of mandelic acid enantiomers followed a pseudo‐second‐order reaction and equilibrium experiments were well fitted to a Langmuir isotherm model. The maximum adsorption capacity of racemic mandelic acid on to the magnetic chiral sorbent was found to be 405 mg g^?1. The magnetic chiral sorbent has a greater affinity for (S)‐(+)‐mandelic acid compared to (R)‐(?)‐mandelic acid. The optimum resolution was achieved with 10 mL 30 mM of racemic mandelic acid and 110 mg of magnetic chiral sorbent. The best percent enantiomeric excess values (up to 64%) were obtained by use of a chiralpak AD‐H column. Chirality 27:835–842, 2015. © 2015 Wiley Periodicals, Inc.     

Analysis of Oxcarbazepine and the 10‐Hydroxycarbazepine Enantiomers in Plasma by LC‐MS/MS: Application in a Pharmacokinetic Study

Oxcarbazepine is a second‐generation antiepileptic drug indicated as monotherapy or adjunctive therapy in the treatment of partial seizures or generalized tonic–clonic seizures in adults and children. It undergoes rapid presystemic reduction with formation of the active metabolite 10‐hydroxycarbazepine (MHD), which has a chiral center at position 10, with the enantiomers (S)‐(+)‐ and R‐(?)‐MHD showing similar antiepileptic effects. This study presents the development and validation of a method of sequential analysis of oxcarbazepine and MHD enantiomers in plasma using liquid chromatography with tandem mass spectrometry (LC‐MS/MS). Aliquots of 100 μL of plasma were extracted with a mixture of methyl tert‐butyl ether: dichloromethane (2:1). The separation of oxcarbazepine and the MHD enantiomers was obtained on a chiral phase Chiralcel OD‐H column, using a mixture of hexane:ethanol:isopropanol (80:15:5, v/v/v) as mobile phase at a flow rate of 1.3 mL/min with a split ratio of 1:5, and quantification was performed by LC‐MS/MS. The limit of quantification was 12.5 ng oxcarbazepine and 31.25 ng of each MHD enantiomer/mL of plasma. The method was applied in the study of kinetic disposition of oxcarbazepine and the MHD enantiomers in the steady state after oral administration of 300 mg/12 h oxcarbazepine in a healthy volunteer. The maximum plasma concentration of oxcarbazepine was 1.2 µg/mL at 0.75 h. The kinetic disposition of MHD is enantioselective, with a higher proportion of the S‐(+)‐MHD enantiomer compared to R‐(?)‐MHD and an AUC^0‐12 _{S‐(+)/R‐(?)} ratio of 5.44. Chirality 25:897–903, 2013. © 2013 Wiley Periodicals, Inc.     

Determination of the Enantiomeric Purity of the Antiasthmatic Drug Montelukast by Means of 1H NMR Spectroscopy

In order to define an enantioselective nuclear magnetic resonance (NMR) method for the antiasthmatic drug montelukast, a series of nine easily available products were evaluated as NMR chiral solvating agents (CSAs): D‐dibenzoyltartaric acid, D‐ditoluoyltartaric acid, (+)‐camphorsulfonic acid, (S)‐BINOL, (S)‐3,3’‐diphenyl‐2,2’‐binaphthyl‐1,1’‐diol, (R)‐3,3'′‐di‐9‐anthracenyl‐1,1'′‐bi‐2‐naphthol, (R)‐3,3'′‐di‐9‐phenanthrenyl‐1,1'′‐bi‐2‐naphthol, Pirkle's alcohol, and (?)‐cinchonidine. It was proved that most of the studied agents constitute diastereomeric complexes with both drug enantiomers in CD₂Cl₂ or CDCl₃ solutions, thus permitting the direct ¹H NMR detection of the unwanted S‐enantiomer, even at levels of 0.75%. (?)‐Cinchonidine was found to be the more convenient CSA in terms of NMR enantiodiscrimination power and ease of experimental requirements. The final method was validated and applied to the fast monitoring of the optical purity of montelukast “in‐process” samples, circumventing the need for tedious and slower analytical procedures like enantioselective chromatography or capillary electrophoresis. In addition, a method for the enantiopurity control of the commercial drug (montelukast sodium salt) was also established using (S)‐BINOL as NMR CSA. Chirality 25: 780–786, 2013. © 2013 Wiley Periodicals, Inc.     

Analysis of carvedilol enantiomers in human plasma using chiral stationary phase column and liquid chromatography with tandem mass spectrometry

Carvedilol is an antihypertensive drug available as a racemic mixture. (?)‐(S)‐carvedilol is responsible for the nonselective β‐blocker activity but both enantiomers present similar activity on α₁‐adrenergic receptor. To our knowledge, this is the first study of carvedilol enantiomers in human plasma using a chiral stationary phase column and liquid chromatography with tandem mass spectrometry. The method involves plasma extraction with diisopropyl ether using metoprolol as internal standard and direct separation of the carvedilol enantiomers on a Chirobiotic T® (Teicoplanin) column. Protonated ions [M + H]⁺ and their respective ion products were monitored at transitions of 407 > 100 for the carvedilol enantiomers and 268 > 116 for the internal standard. The quantification limit was 0.2 ng ml^?1 for both enantiomers in plasma. The method was applied to study enantioselectivity in the pharmacokinetics of carvedilol administered as a single dose of 25 mg to a hypertensive patient. The results showed a higher plasma concentration of (+)‐(R)‐carvedilol (AUC^0–∞ 205.52 vs. 82.61 (ng h) ml^?1), with an enantiomer ratio of 2.48. Chirality, 2012. © 2012 Wiley Periodicals, Inc.     

Enantioselective interaction with acetylcholinesterase of an organophosphate insecticide fenamiphos

Enantioselectivity in the environmental behavior and ecotoxicity of chiral pesticide is widely observed. However, the investigation of the enantioselective mechanisms remains limited. In this study, we used fenamiphos (FAP), an organophosphorus insecticide, to study enantioselectivity in toxicity to arthropods and the inhibition potential towards acetylcholinesterase (AChE) in the rat pheochromocytoma 12 (PC 12) cell line. Furthermore, we carried out molecular docking to help explain the mechanisms of enantioselective toxicity of FAP. The two enantiomers of FAP were successfully separated and identified as R‐(+)‐FAP and S‐(?)‐FAP. Toxicological assays revealed that R‐(+)‐FAP was 2.4‐fold more toxic than S‐(?)‐FAP to Daphnia magna and approximately threefold more to PC12 cells. Based on molecular docking results, dynamic simulation shows that strong hydrophobic interactions and a key hydrogen bond can only exist between R‐(+)‐FAP and AChE, which helps explain the preference of R‐(+) binding to AChE over that of the S‐(?)‐enantiomer, and supports our biological results. Our present study considers the impact of stereochemistry on ecotoxicological effects and, ultimately, on development of environmentally safe, insecticidally efficient pesticides. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Stereoselective Determination of Metoprolol and its Metabolite α‐Hydroxymetoprolol in Plasma by LC‐MS/MS: Application to Pharmacokinetics during Pregnancy

Metoprolol is available for clinical use as a racemic mixture. The S‐(?)‐metoprolol enantiomer is the one expressing higher activity in the blockade of the β₁‐adrenergic receptor. The α‐hydroxymetoprolol metabolite also has activity in the blockade of the β₁‐adrenergic receptor. The present study describes the development and validation of a stereoselective method for sequential analysis of metoprolol and of α‐hydroxymetoprolol in plasma using high‐performance liquid chromatography with tandem mass spectrometry (LC‐MS/MS). 1‐ml aliquots of plasma were extracted with dichloromethane : diisopropyl ether (1:1, v/v). Metoprolol enantiomers and α‐hydroxymetoprolol isomers were separated on a Chiralpak AD column (Daicel Chemical Industries, New York, NY, USA) and quantitated by LC‐MS/MS. The limit of quantitation obtained was 0.2 ng of each metoprolol enantiomer/ml plasma and 0.1 ng/ml of each α‐hydroxymetoprolol isomer/ml plasma. The method was applied to the study of kinetic disposition of metoprolol in plasma samples collected up to 24 h after the administration of a single oral dose of 100‐mg metoprolol tartrate to a hypertensive parturient with a gestational age of 42 weeks. The clinical study showed that the metoprolol pharmakokinetics is enantioselective, with the observation of higher area under the curve (AUC)^0?∞ values for S‐(?)‐metoprolol (AUC_S‐(?)/AUC_R‐(+) = 1.81) and the favoring of the formation of the new chiral center 1′R of α‐hydroxymetoprolol (AUC^0?∞_1′R/1′S = 2.78). Chirality, 25:1–7, 2013. © 2012 Wiley Periodicals, Inc.     

Synthesis of enantiomers of exo‐2‐norbornyl‐N‐n‐butylcarbamate and endo‐2‐norbornyl‐N‐n‐butylcarbamate for stereoselective inhibition of acetylcholinesterase

The acetylcholinesterase inhibition by enantiomers of exo‐ and endo‐2‐norbornyl‐N‐n‐butylcarbamates shows high stereoselelectivity. For the acetylcholinesterase inhibitions by (R)‐(+)‐ and (S)‐(?)‐exo‐2‐norbornyl‐N‐n‐butylcarbamates, the R‐enantiomer is more potent than the S‐enantiomer. But, for the acetylcholinesterase inhibitions by (R)‐(+)‐ and (S)‐(?)‐endo‐2‐norbornyl‐N‐n‐butylcarbamates, the S‐enantiomer is more potent than the R‐enantiomer. Optically pure (R)‐(+)‐exo‐, (S)‐(?)‐exo‐, (R)‐(+)‐endo‐, and (S)‐(?)‐endo‐2‐norbornyl‐N‐n‐butylcarbamates are synthesized from condensations of optically pure (R)‐(+)‐exo‐, (S)‐(?)‐exo‐, (R)‐(+)‐endo‐, and (S)‐(?)‐endo‐2‐norborneols with n‐butyl isocyanate, respectively. Optically pure norborneols are obtained from kinetic resolutions of their racemic esters by lipase catalysis in organic solvent. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Enantioselective Pharmacokinetics of Doxazosin and Pharmacokinetic Interaction Between the Isomers in Rats

In this study, the stereoselective pharmacokinetics of doxazosin enantiomers and their pharmacokinetic interaction were studied in rats. Enantiomer concentrations in plasma were measured using chiral high‐pressure liquid chromatography (HPLC) with fluorescence detection after oral or intravenous administration of (–)‐(R)‐doxazosin 3.0 mg/kg, (+)‐(S)‐doxazosin 3.0 mg/kg, and rac‐doxazosin 6.0 mg/kg. AUC values of (+)‐(S)‐doxazosin were always larger than those of (–)‐(R)‐doxazosin, regardless of oral or intravenous administration. The maximum plasma concentration (C_max) value of (–)‐(R)‐doxazosin after oral administration was significantly higher when given alone (110.5 ± 46.4 ng/mL) versus in racemate (53.2 ± 19.7 ng/mL), whereas the C_max value of (+)‐(S)‐doxazosin did not change significantly. The area under the curve (AUC) and C_max values for (+)‐(S)‐doxazosin after intravenous administration were significantly lower, and its Cl value significantly higher, when given alone versus in racemate. We speculate that (–)‐(R)‐doxazosin increases (+)‐(S)‐doxazosin exposure probably by inhibiting the elimination of (+)‐(S)‐doxazosin, and the enantiomers may be competitively absorbed from the gastrointestinal tract. In conclusion, doxazosin pharmacokinetics are substantially stereospecific and enantiomer–enantiomer interaction occurs after rac‐administration. Chirality 27:738–744, 2015. © 2015 Wiley Periodicals, Inc.     

Stereoselective Degradation of alpha‐Cypermethrin and Its Enantiomers in Rat Liver Microsomes

Alpha‐cypermethrin (α‐CP), [(RS)‐a‐cyano‐3‐phenoxy benzyl (1RS)‐cis‐3‐(2, 2‐dichlorovinyl)‐2, 2‐dimethylcyclopropanecarboxylate], comprises a diastereoisomer pair of cypermethrin, which are (+)‐(1R‐cis‐αS)–CP (insecticidal) and (?)‐(1S‐cis‐αR)–CP (inactive). In this experiment, the stereoselective degradation of α‐CP was investigated in rat liver microsomes by high‐performance liquid chromatography (HPLC) with a cellulose‐tris‐ (3, 5‐dimethylphenylcarbamate)‐based chiral stationary phase. The results revealed that the degradation of (?)‐(1S‐cis‐αR)‐CP was much faster than (+)‐(1R‐cis‐αS)‐CP both in enantiomer monomers and rac‐α‐CP. As for the enzyme kinetic parameters, there were some variances between rac‐α‐CP and the enantiomer monomers. In rac‐α‐CP, the V_max and CL_int of (+)‐(1R‐cis‐αS)–CP (5105.22 ± 326.26 nM/min/mg protein and 189.64 mL/min/mg protein) were about one‐half of those of (?)‐(1S‐cis‐αR)–CP (9308.57 ± 772.24 nM/min/mg protein and 352.19 mL/min/mg protein), while the K_m of the two α‐CP enantiomers were similar. However, in the enantiomer monomers of α‐CP, the V_max and K_m of (+)‐(1R‐cis‐αS) ‐CP were 2‐fold and 5‐fold of (?)‐(1S‐cis‐αR)‐CP, respectively, which showed a significant difference with rac‐α‐CP. The CL_int of (+)‐(1R‐cis‐αS)–CP (140.97 mL/min/mg protein) was still about one‐half of (?)‐(1S‐cis‐αR)–CP (325.72 mL/min/mg protein) in enantiomer monomers. The interaction of enantiomers of α‐CP in rat liver microsomes was researched and the results showed that there were different interactions between the IC₅₀ of (?)‐ to (+)‐(1R‐cis‐αS)‐CP and (+)‐ to (?)‐(1S‐cis‐αR)‐CP(IC_50(?)/(+) / IC_50(+)/(?) = 0.61). Chirality 28:58–64, 2016. © 2015 Wiley Periodicals, Inc.     

Influence of Gasoline Inhalation on the Enantioselective Pharmacokinetics of Fluoxetine in Rats

Fluoxetine is used clinically as a racemic mixture of (+)‐(S) and (–)‐(R) enantiomers for the treatment of depression. CYP2D6 catalyzes the metabolism of both fluoxetine enantiomers. We aimed to evaluate whether exposure to gasoline results in CYP2D inhibition. Male Wistar rats exposed to filtered air (n = 36; control group) or to 600 ppm of gasoline (n = 36) in a nose‐only inhalation exposure chamber for 6 weeks (6 h/day, 5 days/week) received a single oral 10‐mg/kg dose of racemic fluoxetine. Fluoxetine enantiomers in plasma samples were analyzed by a validated analytical method using LC‐MS/MS. The separation of fluoxetine enantiomers was performed in a Chirobiotic V column using as the mobile phase a mixture of ethanol:ammonium acetate 15 mM. Higher plasma concentrations of the (+)‐(S)‐fluoxetine enantiomer were found in the control group (enantiomeric ratio AUC_{(+)‐(S)/(–)‐(R)} = 1.68). In animals exposed to gasoline, we observed an increase in AUC_0‐∞ for both enantiomers, with a sharper increase seen for the (–)‐(R)‐fluoxetine enantiomer (enantiomeric ratio AUC_{(+)‐(S)/(–)‐(R)} = 1.07), resulting in a loss of enantioselectivity. Exposure to gasoline was found to result in the loss of enantioselectivity of fluoxetine, with the predominant reduction occurring in the clearance of the (–)‐(R)‐fluoxetine enantiomer (55% vs. 30%). Chirality 25:206–210, 2013. © 2013 Wiley Periodicals, Inc.     

Influence of N‐hexane inhalation on the enantioselective pharmacokinetics and metabolism of verapamil in rats

Verapamil (VER) is commercialized as a racemic mixture of the (+)‐(R)‐VER and (?)‐(S)‐VER enantiomers. VER is biotransformed into norverapamil (NOR) and other metabolites through CYP‐dependent pathways. N‐hexane is a solvent that can alter the metabolism of CYP‐dependent drugs. The present study investigated the influence of n‐hexane (nose‐only inhalation exposure chamber at concentrations of 88, 176, and 352 mg/m³) on the kinetic disposition of the (+)‐(R)‐VER, (?)‐(S)‐VER, (R)‐NOR and (S)‐NOR in rats treated with a single dose of racemic VER (10 mg/kg). VER and NOR enantiomers in rat plasma was analyzed by LC‐MS/MS (m/z = 441.3 > 165.5 for the NOR and m/z 455.3 > 165.5 for the VER enantiomers) using a Chiralpak® AD column. Pharmacokinetic analysis was performed using a monocompartmental model. The pharmacokinetics of VER was enantioselective in control rats, with higher plasma proportions of the (?)‐(S)‐VER eutomer (AUC^0?∞ = 250.8 vs. 120.4 ng/ml/h; P ≤ 0.05, Wilcoxon test). The (S)‐NOR metabolite was also found to accumulate in plasma of control animals, with an S/R AUC^0?∞ ratio of 1.5. The pharmacokinetic parameters AUC^0?∞, Cl/F, Vd/F, and t_1/2 obtained for VER and NOR enantiomers were not altered by nose‐only exposure to n‐hexane at concentrations of 88, 176, or 352 mg/m³ (P > 0.05, Kruskal‐Wallis test). However, the verapamil kinetic disposition was not enantioselective for the animals exposed to n‐hexane at concentrations equal to or higher than the TLV‐TWA. This finding is relevant considering that the (?)‐(S)‐VER eutomer is 10–20 times more potent than R‐(+)‐VER in terms of its chronotropic effect on atrioventricular conduction in rats and humans. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Bevantolol hydrochloride (nc-1400): Absolute configuration and direct separation of the enantiomers

Synthesis of (?)-bevantolol hydrochloride from 3,4-dimethoxyphenethylamine and (S)-(+)-m-tolyl glycidyl ether derived from (R)-(?)-epichlorohydrin established the absolute configuration of the (+) and (?) enantiomer as R and S, respectively. The purity of the enantiomers was determines using a chiral cellulose column (CHIRALCEL OD®) which allowed direct separation of the enantiomers. A separation factor (α) of 4.20 and a resolution factor (Rs) of 9.21 were obtained. © 1995 Wiley-Liss, Inc.     

Enantioseparation and Determination of the Chiral Fungicide Furametpyr Enantiomers in Rice,Soil, and Water by High‐Performance Liquid Chromatography

The chiral fungicide furametpyr is widely used in the rice field to control rice sheath blight; however, furametpyr enantiomers are treated as just one compound in traditional achiral analysis, which gives only partial information. An effective chiral analytical method was developed for the resolution and determination of the fungicide furametpyr enantiomers in rice, soil, and water samples. Furametpyr enantiomers were excellently separated and determined on a Chiralpak AD‐H column with n‐hexane/ethanol (90:10, v/v) as mobile phase at a flow rate of 0.8 mL min^‐1 with UV detection at 220 nm. The resolution was up to 8.85. The first eluted enantiomer was (+)‐furametpyr and the second eluted one was (?)‐furametpyr. The effects of mobile‐phase composition and column temperature on the enantioseparation were evaluated. The method was validated for linearity, repeatability, accuracy, limit of detection (LOD), and limit of quantification LOQ. LOD was 2.0 µg kg^‐1 in water, 0.02 mg kg^‐1 in soil, and 0.07 mg kg^‐1 in rice with an LOQ of 6.7 µg kg^‐1 in water, 0.07 mg kg^‐1 in soil, and 0.23 mg kg^‐1 in rice. The average recoveries of the pesticide in all matrices ranged from 73.1 to 101.8% for all fortification levels. The precision values associated with the analytical method, expressed as relative standard deviation (RSD) values, were below 14.0% in all matrices. The methodology was successfully applied for the enantioselective analysis of furametpyr enantiomers in real samples. Chirality 25:904–909, 2013. © 2013 Wiley Periodicals, Inc.