Chiral Inversion Research Articles

A Chiral Polycyclic Aromatic Hydrocarbon Monkey Saddle

AbstractA contorted polycyclic aromatic hydrocarbon (PAH) in the shape of a monkey saddle has been synthesized in three steps from a readily available truxene precursor. The monkey saddle PAH is consisting of three five‐, seven six‐, and three eight‐membered rings and has been unambiguously characterized by single‐crystal X‐ray diffraction. Owing to the three biaryl axes the monkey saddle PAH is inherently chiral. The inversion of the two enantiomeric structures into each other preferably occurs through a twisting of peripheral rings rather than by a fully planar intermediate, as has been calculated by DFT methods. Enantiomers were separated by chiral HPLC and inversion barriers determined by variable temperature circular dichroism spectroscopy, supporting the twisting mechanism.

A Chiral Polycyclic Aromatic Hydrocarbon Monkey Saddle.

A contorted polycyclic aromatic hydrocarbon (PAH) in the shape of a monkey saddle has been synthesized in three steps from a readily available truxene precursor. The monkey saddle PAH is consisting of three five‐, seven six‐, and three eight‐membered rings and has been unambiguously characterized by single‐crystal X‐ray diffraction. Owing to the three biaryl axes the monkey saddle PAH is inherently chiral. The inversion of the two enantiomeric structures into each other preferably occurs through a twisting of peripheral rings rather than by a fully planar intermediate, as has been calculated by DFT methods. Enantiomers were separated by chiral HPLC and inversion barriers determined by variable temperature circular dichroism spectroscopy, supporting the twisting mechanism.

Analysis of endogenous epinephrine and norepinephrine enantiomers in rat plasma and application to a stereoselective pharmacokinetics

Epinephrine and norepinephrine are a class of chiral endogenous catecholamines, which are known as major neurotransmitters. This work described a new LC–MS/MS method coupled with pre-column derivatization, enabling the simultaneous enantiomeric separation of epinephrine and norepinephrine in rat plasma. After protein precipitation procedure, the samples were derivatized with (S)-N-(4-nitrophenoxycarbonyl) phenylalanine methoxyethyl ester, [(S)-NIFE]. The derivatives resolved with good baseline separation on an ACQUITY UPLC BEH C18 column (100 mm × 2.1 mm, 1.7 μm) with mobile phase composed of methanol with 0.2% formic acid in water at a flow rate of 0.2 mL/min. Analysis was performed by multiple reaction monitoring in positive ionization mode. The linear ranges were 1.0–500 ng/mL for epinephrine enantiomers and 1.5–750 ng/mL for norepinephrine enantiomers. The lower limits of quantification for epinephrine and norepinephrine enantiomers were 1.0 and 1.5 ng/mL, respectively. The intra-day and inter-day precision were all less than 10.7% and accuracy ranged from 96.0 to 101.5%. Recoveries for all the analytes were more than 80.3%. The proposed method was successfully applied to simultaneously determine endogenous epinephrine and norepinephrine enantiomers in rat plasma. l-epinephrine and l-norepinephrine were sensitively and accurately quantified while both the d-enantiomers were not detected. Additionally, epinephrine enantiomers were analyzed for stereoselective pharmacokinetics in rats after intravenous administration of racemic epinephrine for the first time. The pharmacokinetic results indicated that the disposition of epinephrine enantiomers was stereoselective and chiral inversion did not occur in rats.

Supramolecular Nanopumps with Chiral Recognition for Moving Organic Pollutants from Water.

Since organic pollutants in water resources have raised concerns on aquatic ecosystems and human health, mechanical machines such as a nanopump for rapid and efficient removal of pollutants from water with regeneration properties remains a challenge. Here, a pH-responsive artificial pump from left-handed porous tubules into right-handed solid fibers was presented by the self-assembly of bent-shaped aromatic amphiphiles. The bent-shaped amphiphile with a pH-sensitive segment was demonstrated in aromatic hexameric macrocycles, which could contract into dimeric disks. Such a switchable aromatic pore with superhydrophobicity was well-suited for an efficient removal and controlled release of organic pollutants from water through pulsating motion. The removal efficiency is found to be 78% for ethinyloestradiol and 82% for bisphenol. Additionally, the pumping accompanied by chiral inversion was endowed with a rapid removal and convenient regenerable ability. The inflation from right-handed solid fibers into left-handed tubules for efficient removal pollutants was remarkably promoted by (-)-acidic enantiomer of malic acid, whereas the contraction with full desorption of pollutants was incisively responsive to alkaline with (+)-conformation. The kinetically regulable porous device with a chiral recognition will provide a promising platform for the construction of rapid responsible machine for sewage treatment.

Stereoselective supercritical fluidic chromatography –mass spectrometry (SFC-MS) as a fast bioanalytical tool to assess chiral inversion in vivo and in vitro

The stereoisomers of a chiral drug can exhibit great differences in pharmacodynamic and/or pharmacokinetic properties. Chiral bioanalytical assays are necessary to measure the concentrations of individual enantiomers and/or their chiral metabolites in biological samples in order to assess the absorption, distribution, metabolism, excretion, and toxicity of the individual enantiomers. In addition, chiral assays are required to evaluate potential chiral inversion caused by the biotransformation process. While normal phase or reversed phase chromatography remains the common choices for chiral bioanalytical assays, supercritical fluid chromatography (SFC) demonstrated shorter analysis time without affecting separation efficiency, due to the lower viscosity and faster mass transfer properties of supercritical or subcritical carbon dioxide than traditionally used mobile phases. In this paper, we present examples for developing chiral SFC-multiple reaction monitoring (MRM) assays to measure the pharmacokinetic profiles of stereoisomers of drugs in three distinct cases. Furthermore, these assays can be used to investigate the potential chiral inversion of the small molecule drugs from in vivo or in vitro sources.

Chiral Inversion of Amino Acids in Antiparallel β-Sheets at Interfaces Probed by Vibrational Sum Frequency Generation Spectroscopy.

A parallel study of protein variants with all (l-), all (d-), or mixed (l-)/(d-) amino acids can be used to assess how backbone architecture versus side chain identity determines protein structure. Here, we investigate the secondary structure and side chain orientation dynamics of the antiparallel β-sheet peptide LK7β (Ac-Leu-Lys-Leu-Lys-Leu-Lys-Leu-NH2) composed of all (l-), all (d-), or alternating (l-Leu)/(d-Lys) amino acids. Using interface-selective vibrational sum frequency generation spectroscopy (VSFG), we observe that the alternating (l-)/(d-) peptide lacks a resonant C-H stretching mode compared to the (l-) and (d-) variants and does not form antiparallel β-sheets. We rationalize our observations on the basis of density functional theory calculations and molecular dynamics (MD) simulations of LK7β at the air-water interface. Irrespective of the handedness of the amino acids, leucine side chains prefer to orient toward the hydrophobic air phase while lysine side chains prefer the hydrophilic water phase. These preferences dictate the backbone configuration of LK7β and thereby the folding of the peptide. Our MD simulations show that the preferred side chain orientations can force the backbone of a single strand of (l-) LK7β at the air-water interface to adopt β-sheet Ramachandran angles. However, denaturation of the β-sheets at pH = 2 results in a negligible chiral VSFG amide I response. The combined computational and experimental results lend critical support to the theory that a chiral VSFG response requires macroscopic chirality, such as in β-sheets. Our results can guide expectations about the VSFG optical responses of proteins and should improve understanding of how amino acid chirality modulates the structure and function of natural and de novo proteins at biological interfaces.

NMR investigation of photoinduced chiral inversion in (R)/(S)-naproxen–(S)-tryptophan linked system

The inversion of the chiral centers in (R)/(S)-naproxen–(S)-tryptophan linked system under UV irradiation has been detected by the 1H NMR spectroscopy as an example of the (R,S)-diastereomer transformation into (S,S) analogue in an achiral environment.

A generalized Holling type II model for the interaction between dextral-sinistral snails and Pareas snakes

Pareatic snakes possess outstanding asymmetry in the mandibular tooth number, which has probably been caused by its evolution to improve the feeding on the predominant dextral snails. Gene mutation can generate chiral inversion on the snail body. A sinistral snail population can thrive in this ecological context. The interactions between dextral/sinistral snails and Pareas snakes are modeled in this paper by using a new generalized functional response of Holling type II. Distinct Pareas species show different bilateral asymmetry degrees. This parameter plays an essential role in our model and determines the evolution of the populations. Stability of the solutions is also analyzed for different regimes in the space of parameters.

Mechanism of Reductive Metabolism and Chiral Inversion of Proton Pump Inhibitors.

Racemic proton pump inhibitors (PPIs) have been developed into pure enantiomers given superior pharmacokinetic profiles. However, after doses of single enantiomer PPIs, different degrees of chiral inversion were observed. We investigated the relationship between chiral inversion and reductive metabolism of PPIs, as well as the mechanism of reductive metabolism. In liver microsomes and Sprague-Dawley rats, PPI thioethers were stereoselectively oxidized to (R)- and (S)-PPIs, indicating that thioethers could be the intermediates of chiral inversion. By comparing the area under the plasma concentration-time curve ratios of thioether to rabeprazole under different routes of administration and blood sampling site, it was determined that thioether was mainly formed in the liver rather than the intestine. The formation rate of PPI thioethers in liver subcellular fractions was significantly higher than that in buffers. Sulfhydryl-blocking agents, such as N-ethylmaleimide, menadione, and ethacrynic acid, inhibited the reductive metabolism of PPIs in vitro, and their corresponding glutathione conjugates were observed. Similar amounts of thioethers were formed in glutathione solutions as in liver subcellular fractions, indicating that biologic reducing agents, instead of reductases, accelerated the reductive metabolism of PPIs. The reduction rates in glutathione solutions were ordered as follows: rabeprazole > omeprazole > lansoprazole > pantoprazole, which was consistent with the natural bond orbital charges of sulfur atoms in these compounds. In conclusion, PPIs were transformed into thioethers by biologic reducing agents in liver, and thioethers continued to be oxidized to two enantiomers, leading to chiral inversion. Furthermore, inhibiting oxidative metabolism of PPIs enhanced reductive metabolism and chiral inversion.

Chiral Inversion of Thiolate-Protected Gold Nanoclusters via Core Reconstruction without Breaking a Au-S Bond.

On the basis of density functional theory computations of the well-known chiral Au38(SR)24 nanocluster and its Pd- and Ag-doped derivatives, we propose here a mechanism for chiral inversion that does not require the breaking of a metal–sulfur bond at the metal–ligand interface but features a collective rotation of the gold core. The calculated energy barriers for this mechanism for Au38 and Pd-doped Au38 are in the range of 1–1.5 eV, significantly lower than barriers involving the breakage of Au–S bonds (2.5 eV). For Ag-doped Au38, barriers for both mechanisms are similar (1.3–1.5 eV). Inversion barriers for a larger chiral Au144(SR)60 are much higher (2.5−2.8 eV). Our computed barriers are in good agreement with racemization barriers estimated from existing experiments for bare and doped Au38. These results highlight the sensitivity of chiral inversion to the size, structure, and metal composition of the metal core and sensitivity to the detailed structure of the metal–thiolate interface. Our work also predicts that enantiopure Au144(SR)60 clusters would be promising materials for applications requiring high resistance to chiral inversion.

Bulk-boundary correspondence in a non-Hermitian system in one dimension with chiral inversion symmetry

Asymmetric coupling amplitudes effectively create an imaginary gauge field, which induces a non-Hermitian Aharonov-Bohm (AB) effect. Nonzero imaginary magnetic flux invalidates the bulk-boundary correspondence and leads to a topological phase transition. However, the way of non-Hermiticity appearance may alter the system topology. By alternatively introducing the non-Hermiticity under symmetry to prevent nonzero imaginary magnetic flux, the bulk-boundary correspondence recovers and every bulk state becomes extended; the bulk topology of Bloch Hamiltonian predicts the (non)existence of edge states and topological phase transition. These are elucidated in a non-Hermitian Su-Schrieffer-Heeger model, where chiral-inversion symmetry ensures the vanishing of imaginary magnetic flux. The average value of Pauli matrices under the eigenstate of chiral-inversion symmetric Bloch Hamiltonian defines a vector field, the vorticity of topological defects in the vector field is a topological invariant. Our findings are applicable in other non-Hermitian systems. We first uncover the roles played by non-Hermitian AB effect and chiral-inversion symmetry for the breakdown and recovery of bulk-boundary correspondence, and develop new insights for understanding non-Hermitian topological phases of matter.

Topological edge states with skin effect in a trimerized non-Hermitian lattice

In recent years, exploring new topological quantum model structures and in depth analyzing the novel physical properties in various multimerized topological lattices have become a hot topic in the field of quantum optics. Among the different model structures, the multimerized non-Hermitian lattice controlled by different parameters in the future research of topological quantum materials, we believe, can exhibit more meaningful novel topological properties. As one of the most classic topological models, the one-dimensional Aubry-André-Harper (AAH) model has received more and more attention in the study of multimerized lattices. In this paper, we focus on the novel topological properties of a trimerized non-Hermitian lattice, and extend the trimer model structure from a one-dimensional chain to a quasi-one-dimensional zigzag structure. The results show that firstly, if the nearest-neighbor forward coupling coefficient in the unit cell is not equal to the backward coupling coefficient, the chiral inversion symmetry of the system is destroyed. It can be observed that the bulk states and the edge states in the trimerization model will be localized on the same edge of the lattice, and the skin effect will appear in the system. With the increase of the nearest-neighbor coupling coefficient, the width of the edge state changes in which the lower edge state of the imaginary part of the spectrum is narrowed until it disappears. The degree of degeneracy of the system changes, and the number of edge states is reduced from four to two. Remarkably, the generalized bulk-boundary correspondence is shown in certain non-Hermitian topological systems. Secondly, when the trimerization model considers the influence of the next-nearest-neighbor coupling, the numerical results show that the upper and lower energy gaps in the energy spectrum and the edge states in the energy spectrum are asymmetrical as the next-nearest-neighbor coupling coefficient is modulated in an appropriate range. The upper energy gaps and the edge states are narrowed, and the edge states of the lower energy gaps are widened. At the same time, the novel topology features of the system can also be used to achieve the quantitative control of the energy spectrum edge states, and other interesting directions are worth exploring.

Enantioselective LC‐ESI‐MS/MS determination of dropropizine enantiomers in rat plasma and application to a pharmacokinetic study

We developed and validated a simple, sensitive, selective and reliable LC-ESI-MS/MS method for direct quantitation of dropropizine enantiomers namely levodropropizine (LDP) and dextrodropropizine (DDP) in rat plasma without the need for derivatization as per regulatory guidelines. Dropropizine enantiomers and carbamazepine (internal standard) were extracted from 50 μL rat plasma using ethyl acetate. LDP and DDP resolved with good baseline separation (Rs = 4.45) on a Chiralpak IG-3 column. The mobile phase consisted of methanol with 0.05% diethylamine pumped at a flow rate of 0.5 mL/min. Detection and quantitation were done in multiple reaction monitoring mode following the transitions m/z 237 → 160 and 237 → 194 for dropropizine enantiomers and the internal standard, respectively, in the positive ionization mode. The proposed method provided accurate and reproducible results over the linearity range of 3.23-2022 ng/mL for each enantiomer. The intra- and inter-day precisions were in the ranges of 3.38-13.6 and 5.11-13.8 for LDP and 4.19-11.8 and 8.89-10.1 for DDP. Both LDP and DDP were found to be stable under different stability conditions. The method was successfully used in a stereoselective pharmacokinetic study of dropropizine enantiomers in rats following oral administration of racemate dropropizine at 100 mg/kg. The pharmacokinetic results indicate that the disposition of dropropizine enantiomers is not stereoselective and chiral inversion does not occur in rats.

Dynamic Rotational Motions of Vaulted Chiral trans‐Bis(salicylaldiminato)palladium(II) Complexes Bearing Rigid or Flexible Carbon Chain Linkers

Planar chiral, trans‐bis(salicylaldiminato)palladium(II) complexes having a macrocyclic vaulting structure consisting of either a heptamethylene‐butadiynylene‐heptamethylene (1) or polymethylene (2) bridge were synthesized and subsequently characterized by NMR, IR, high‐resolution mass spectrometry, and single crystal XRD. The dynamic rotational behaviors of these vaulted complexes resulting from a skipping‐rope‐like molecular motion were examined on the basis of kinetic studies of the racemization of the optically pure (100 % ee) complexes. The chiral inversion rate was found to be significantly affected by the conformational flexibility of the complexes, which in turn could be controlled by adjusting the linker length, the linker rigidity, and the ligation properties of the solvent.

Stereoselective pharmacokinetics of (R)-(+)- and (S)-(-)-rabeprazole in human using chiral LC-MS/MS after administration of rabeprazole sodium enteric-coated tablet.

Rabeprazole is an effective proton pump inhibitor to treat acid-related diseases. To achieve the simultaneous determination of rabeprazole enantiomers in human plasma, a chiral LC-MS/MS method was developed and validated. Acetonitrile including 0.1% ammonium were used as protein precipitating agent. Analytes were separated within 8minutes on a Chiralpak IC column (4.6mm×150mm, 5μm). The mobile phase was 10mM ammonium acetate including 0.2% acetic acid-acetonitrile (35:65, v/v). An API 4000 mass spectrometer was used as detector for the analysis, and the multiple reactions monitoring transitions of m/z 360.1→242.2 and 346.1→198.1 were opted for quantifying rabeprazole enantiomers and internal standard. Matrix effects were not apparent for each enantiomer and internal standard (esomeprazole), the calibration curves were linear over the concentration of 0.500 to 400ng·mL-1 , the intra-run precisions were below 5.4%, the inter-run precisions were below 9.9%, and the accuracy was between -9.2% and 9.3%. There was no chiral inversion observed during sample storage, preparation procedure, and analysis, demonstrating that analytes were stable in this study. This method was applied to the stereoselective pharmacokinetic study of (R)-(+)- and (S)-(-)-rabeprazole after oral administration of 10-mg rabeprazole sodium enteric-coated tablet in healthy Chinese subjects.

Stereoselective environmental behavior and biological effect of the chiral organophosphorus insecticide isofenphos‑methyl

The enantiomeric environmental behaviors, bioactivities and toxicities of isofenphos‑methyl enantiomers were characterized systematically in this study. (R)‑Isofenphos‑methyl was degraded preferentially in Yangtze River water and different types of vegetables with an enantiomeric fraction (EF) of 0.6 to 0.96. However, (R)‑isofenphos‑methyl was amplified in both Nanjing (EF = 0.32) and Nanchang (EF = 0.27) soil. Our investigations found that there no bidirectional chiral inversion occurred in either Yangtze River water or soils. The bioactivity of (S)‑isofenphos‑methyl was higher than that of its (R)‑enantiomer against different insect targets, such as Meloidogyne incognita, Nilaparvata lugens, Plutella xylostella and Macrosiphum pisi (3.7 to 149 times). (S)‑Isofenphos‑methyl showed higher toxicity for the nontarget organism (1.1 to 32 times). However, (R)‑isofenphos‑methyl possesses 4.0 times more potency than the (S)-form for the nontarget soil organism Eisenia foetida. This study generally could provide more scientific guidance for the corresponding risk assessments of pesticides in addition to providing a new theoretical basis for scientifically and rationally using isofenphos‑methyl.

Enantioselective analysis of lansoprazole in rat plasma by LC–MS/MS: Application to a stereoselective pharmacokinetic study

A rapid, sensitive and enantioselective method was developed and fully validated for the separation and determination of lansoprazole enantiomers in rat plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The analytes and the internal standard (esomeprazole) were both extracted from plasma samples by liquid-liquid extraction with diethyl ether-dichloromethane (70:30; v/v). Satisfactory resolution (Rs = 2.0) was achieved within 7.3 min on a Chiralpak ID column (250 × 4.6 mm, 5 μm) employing acetonitrile-water (60:40, v/v) as the mobile phase at a flow rate of 0.6 mL/min. The acquisition of mass spectrometric data was performed in the multiple reaction monitoring mode coupled with a positive electrospray ionization source. A comprehensive validation of this method was rigorously conducted over the concentration range of 1.00-500.0 ng/mL for both enantiomers. All of the validation data demonstrated that the desirable linearity, sensitivity, accuracy, precision, recovery and stability were attained from the proposed approach. The established method was successfully applied to a stereoselective pharmacokinetic study of lansoprazole enantiomers in rat plasma after oral administration of 3 mg/kg racemic lansoprazole or dexlansoprazole. No chiral inversion was observed during the experimental procedure.

A Key Factor Dominating the Competition between Photolysis and Photoracemization of [Ru(bipy)3]2+ and [Ru(phen)3]2+ Complexes.

Photolysis and photoracemization are two important photochemical phenomena of the prototype complexes [Ru(bipy)3]2+ and [Ru(phen)3]2+ (bipy = 2,2'-bipyridine, phen = 1,10-phenanthroline), but little is known about their relations. To solve this issue, the photoinduced chiral inversion Δ⇌Λ of the complexes was analyzed theoretically. The results indicated that the photoracemization reaction proceeds on the lowest triplet potential energy surface in three steps 3CTΔ↔3MCΔ, 3MCΔ↔3MCΛ, and 3MCΛ↔3CTΛ (CT = charge transfer state; MC = metal-centered state). Where the first and third steps are fast processes of picoseconds, the second is the rate-determining step (RDS) of microseconds. Such a slow step for the racemization leads to the excited molecule lingering around the bottom of 3MC state after the first step and, therefore, greatly enhances the possibility of deexcitation and photolysis mostly at the triplet-singlet crossing point. In other words, the photoracemization and photolysis of the complexes have a competition relation, not a slave relation as assumed by the photoracemization model suggested in literature. They are dominated by the RDS. This conclusion is also consistent with the Δ(δ S)⇌Λ(δ S) chiral inversion of the [Ru(bipy)2(L-ser)]+ series complexes, which is reversible with no detectable photolysis, as its second step is a fast one. Note that, although the photoracemization of the prototype complexes is very slow, it passes through the three steps reversibly and ends with a photon emitting, which could be detected with the time-resolved circularly polarized luminescence and related techniques. These findings are helpful to understand and control the photochemical behavior of the complexes in practice.

Pseudo[1]Catenane-Type Pillar[5]thiacrown Whose Planar Chiral Inversion is Triggered by Metal Cation and Controlled by Anion.

Chiral inversion of single molecules has been a challenging task because chirality information controls structures and functions of various molecules, artificial nanostructures, DNA, and proteins. Herein we present a pseudo[1]catenane-type molecule whose planar chiral inversion is driven by a metal ion under the control of anions for the first time. Considering an in-out equilibrium of a fused thiacrown and the soft metal binding, pillar[5]thiacrown ( rac-L) was synthesized. Two planar-chiral enantiomers of rac-L ( in-pS-L and in-pR-L) were isolated and the absolute configuration was determined by circular dichroism and single crystal X-ray analysis. The in-pS-L recognizes Hg2+ to trigger the chiral inversion to out-pR-L, to our surprise; it takes place only in the presence of ClO4- or NO3- among the anions used. In the mercury(II) perchlorate complex solution, anion-exchange from ClO4- to I- or removal of Hg2+ by addition of S2- makes the system reversible. The crystallographic approach reveals that the anions act as coordination mode-directing species ( endo- or exo-coordination) which play a decisive role on the chiral inversion. For instance, the week coordinating ClO4- allows Hg2+ to locate inside the thiacrown ( endo-coordination) which causes the chiral inversion from in-pS-L to out-pR-L due to the expansion of the thiacrown unit upon endo-mode complexation. Oppositely, the strong coordinating I- takes Hg2+ out of the thiacrown ( exo-coordination) without large conformational changes of the thiacrown, resulting in no chiral inversion. A series of experimental works was also accomplished with the other enantiomer in-pR-L, which afforded identical results. Consequently, the chiral inversion is governed by steric factors that arise from the coordination modes depending on the coordinating ability of anions. This work demonstrates the first chiral inversion induced by combination of metal ion and anion and presents a new perspective on the supramolecular coordination chemistry of pillar[ n]arenes.

Mutual inversion of flurbiprofen enantiomers in various rat and mouse strains.

Flurbiprofen (F) is a nonsteroidal anti-inflammatory drug (NSAID) used therapeutically as the racemate of (R)-enantiomer and (S)-enantiomer. The inversion of RF to SF and vice versa was investigated in C57Bl/6 and SJL mice and Dark Agouti and Lewis rats. The enzyme α-methylacyl-CoA racemase (AMACR) is involved in the chiral inversion pathway that converts members of the 2-arylpropionic acid NSAIDs from the R-enantiomer to the S-enantiomer. We studied C57Bl/6 mice deficient in AMACR postulating that they should show reduced inversion of RF to SF. In line with the data of others in mice, (R)-inversion to (S)-inversion was relatively high in both the C57Bl/6 and SJL mice (fraction inverted, FI =37.7% and 24.7%, respectively). In contrast, in AMACR deficient mice, there was no measurable peak for SF after administration of RF. The results in both rat strains (Dark Agouti and Lewis rats, FI =1.4% and 4.1%, respectively) confirm the low chiral inversion of the enantiomers of flurbiprofen in the rat, as observed by other authors in the Sprague-Dawley strain (<5%). From the present results, we conclude that for the study of flurbiprofen enantiomers, the rat is more suitable than the mouse as a model for the human in which (R)-inversion to (S)-inversion is negligible.