Interaction Of Enantiomers Research Articles

Simultaneous Physical Cross-Linking and Mechanical Strengthening of Elastomers by Enantiomeric Interactions through Reactive Processing

Simultaneous Physical Cross-Linking and Mechanical Strengthening of Elastomers by Enantiomeric Interactions through Reactive Processing

A design of experiments screen reveals that Clostridium novyi-NT spore germinant sensing is stereoflexible for valine and its analogs

Although Clostridium novyi-NT is an anti-cancer bacterial therapeutic which germinates within hypoxic tumors to kill cancer cells, the actual germination triggers for C. novyi-NT are still unknown. In this study, we screen candidate germinants using combinatorial experimental designs and discover by serendipity that D-valine is a potent germinant, inducing 50% spore germination at 4.2 mM concentration. Further investigation revealed that five D-valine analogs are also germinants and four of these analogs are enantiomeric pairs. This stereoflexible effect of L- and D-amino acids shows that spore germination is a complex process where enantiomeric interactions can be confounders. This study also identifies L-cysteine as a germinant, and hypoxanthine and inosine as co-germinants. Several other amino acids promote (L-valine, L-histidine, L-threonine and L-alanine) or inhibit (L-arginine, L-glycine, L-lysine, L-tryptophan) germination in an interaction-dependent manner. D-alanine inhibits all germination, even in complex growth media. This work lays the foundation for improving the germination efficacy of C. novyi-NT spores in tumors.

Synergistic effects of chain dynamics and enantiomeric interaction on the crystallization in PDLA/PLLA mixtures

Intra- and inter-molecular interactions play an important role in polymer chain dynamics. Polymer crystallization behavior and crystalline structure are affected by the chain dynamics. The enantiomer containing PLLA and PDLA is considered as an important nucleation for PLA crystallization since it was found. The mixtures containing PDLA and stereocomplex (SC) crystal were prepared via different solvents or without any solvent. The effect of the stereocomplex promoted homopolymer crystallization and the non-isothermal crystallization behaviors of the prepared mixtures were characterized by DSC. The DSC results showed that the crystallization temperature of the homopolymer in the PDLA/SC mixtures increases with the stereocomplex contents as cooling from 200 °C at 10 °C/min. The increased crystallization temperature reduces with decreasing of cooling rate, and the increasing is even negligible when the cooling rate is 1 °C/min or lower. The promoted crystallization behavior could be influenced by melting temperature and melting time. FTIR results indicated the CH3⋯O interactions between the enantiomers of polylactide is related to the solvents with different solubility parameters for sample preparations. The stereocomplex effect on the PDLA crystallization in the mixtures was discussed based on the molecular interactions between enantiomers and chain dynamics in presence of obstacles.

Insights into Praziquantel Metabolism and Potential Enantiomeric Cytochrome P450-Mediated Drug-Drug Interaction.

The active enantiomer R-Praziquantel (PZQ) shows a clinically lower relative exposure when administered enantiomerically pure compared with a racemic form. We investigated the hypothesis that enantiomer-enantiomer interactions on cytochrome P450 (P450) enzymes could explain this observation and aimed to further deepen the understanding of PZQ metabolism. First, in an in vitro metabolite profiling study, the formation of multiple metabolites per P450, together with an observed interconversion of cis-4'-OH-PZQ to trans-4'-OH-PZQ in human hepatocytes, pointed out the inadequacy of measuring metabolite formation in kinetic studies. Thus, a substrate depletion approach to study PZQ enantiomeric interactions was applied. Second, an abundant CYP3A4 metabolite found in previous studies was structurally characterized. Third, substrate depletion methodologies were applied to determine P450 enzyme kinetics of PZQ and to further estimate enantiomer-enantiomer inhibitory parameters. A competitive inhibition between PZQ enantiomers for CYP2C9, 2C19, 3A4, and 3A5 was revealed. Analyses considering the clearance of only one or both enantiomers provided comparable enantiomer-enantiomer inhibition estimates. To conclude, this paper provides new insights into PZQ metabolic profile to enable a better understanding of enantioselective pharmacokinetics using substrate depletion-based methods. SIGNIFICANCE STATEMENT: In this study, enantiomer-enantiomer interactions of praziquantel on cytochrome P450 metabolizing enzymes are investigated via substrate depletion measurement using modeling methods. Together with new insights into the praziquantel metabolism, this work provides a novel data set to understand its pharmacokinetics.

Chirality Induction in Crystalline Solids Containing Sandwich-type [Ln(α2-P2W17O61)2]17- Polyoxotungstates and Proline.

Chiral crystalline compounds of the series of [Ln(α2-P2W17O61)2]17- polyanions embracing nearly all the lanthanide (Ln) ions were successfully isolated using Pro (proline) as a chiral director. In each compound, the polyanion and Pro were associated through a stereoselective interaction involving N(H)···O hydrogen bonding. 31P NMR and circular dichroism studies revealed the induction of chirality by Pro in the racemic aqueous systems of the [Ln(α2-P2W17O61)2]17- polyanions, i.e., the Pfeiffer effect. Mechanistically, this racemization was regulated by competitive enantiomeric interactions between the l-/d-Pro and l-/d-polyanions, with only one racemization route (the on-site rotation of the [α2-P2W17O61)]10- unit) observed, independent of the nature of Ln.

On chirality induction in the crystalline solid-containing sandwich-type [Ln(α-PW11O39)2]11−polyoxotungstate and proline

For the racemisation, the [Ln(α-PW11O39)2]11−polyanion with light Ln experienced the ‘on-site rotation’ mechanism, while the [Ln(α-PW11O39)2]11−polyanion with heavy Ln followed the “dissociation–association” mechanism.

Enantiomeric interactions between liquid crystals and organized monolayers of tyrosine-containing dipeptides.

We have examined the orientational ordering of nematic liquid crystals (LCs) supported on organized monolayers of dipeptides with the goal of understanding how peptide-based interfaces encode intermolecular interactions that are amplified into supramolecular ordering. By characterizing the orientations of nematic LCs (4-cyano-4'-pentylbiphenyl and TL205 (a mixture of mesogens containing cyclohexane-fluorinated biphenyls and fluorinated terphenyls)) on monolayers of l-cysteine-l-tyrosine, l-cysteine-l-phenylalanine, or l-cysteine-l-phosphotyrosine formed on crystallographically textured films of gold, we conclude that patterns of hydrogen bonds generated by the organized monolayers of dipeptides are transduced via macroscopic orientational ordering of the LCs. This conclusion is supported by the observation that the ordering exhibited by the achiral LCs is specific to the enantiomers used to form the dipeptide-based monolayers. The dominant role of the -OH group of tyrosine in dictating the patterns of hydrogen bonds that orient the LCs was also evidenced by the effects of phosphorylation of the tyrosine on the ordering of the LCs. Overall, these results reveal that crystallographic texturing of gold films can direct the formation of monolayers of dipeptides with long-range order, thus unmasking the influence of hydrogen bonding, chirality, and phosphorylation on the macroscopic orientational ordering of LCs supported on these surfaces. These results suggest new approaches based on supramolecular assembly for reporting the chemical functionality and stereochemistry of synthetic and biological peptide-based molecules displayed at surfaces.

Long-Range Chiral Recognition due to Substrate Locking and Substrate-Adsorbate Charge Transfer

First-principles calculations are used to rationalize the long-range chiral recognition between adenine and phenylglycine adsorbed on Cu(110) [Chen and Richardson, Nature Mater. 2, 324 (2003)10.1038/nmat878]. The enantiomeric interaction is traced to substrate-mediated Coulomb repulsion and template effects. The mechanism revealed here (i) shows that the Easson and Stedman model for chiral recognition may include long-range electrostatic interactions and (ii) illustrates the catalytic potential of the substrate for molecular self-assembly.

Enantiomeric Metabolic Interactions and Stereoselective Human Methadone Metabolism

Methadone is administered as a racemate, although opioid activity resides in the R-enantiomer. Methadone disposition is stereoselective, with considerable unexplained variability in clearance and plasma R/S ratios. N-Demethylation of methadone in vitro is predominantly mediated by cytochrome P450 CYP3A4 and CYP2B6 and somewhat by CYP2C19. This investigation evaluated stereoselectivity, models, and kinetic parameters for methadone N-demethylation by recombinant CYP2B6, CYP3A4, and CYP2C19, and the potential for interactions between enantiomers during racemate metabolism. CYP2B6 metabolism was stereoselective. CYP2C19 was less active, and stereoselectivity was opposite that for CYP2B6. CYP3A4 was not stereoselective. With all three isoforms, enantiomer N-dealkylation rates in the racemate were lower than those of (R)-(6-dimethyamino-4,4-diphenyl-heptan-3-one) hydrochloride (R-methadone) or (S)-(6-dimethyamino-4,4-diphenyl-heptan-3-one) hydrochloride (S-methadone) alone, suggesting an enantiomeric interaction and mutual metabolic inhibition. For CYP2B6, the interaction between enantiomers was stereoselective, with S-methadone as a more potent inhibitor of R-methadone N-demethylation than R-of S-methadone. In contrast, enantiomer interactions were not stereoselective with CYP2C19 or CYP3A4. For all three cytochromes P450, methadone N-demethylation was best described by two-site enzyme models with competitive inhibition. There were minor model differences between cytochromes P450 to account for stereoselectivity of metabolism and enantiomeric interactions. Changes in plasma R/S methadone ratios observed after rifampin or troleandomycin pretreatment in humans in vivo were successfully predicted by CYP2B6- but not CYP3A4-catalyzed methadone N-demethylation. CYP2B6 is a predominant catalyst of stereoselective methadone metabolism in vitro. In vivo, CYP2B6 may be a major determinant of methadone metabolism and disposition, and CYP2B6 activity and stereoselective metabolic interactions may confer variability in methadone disposition.

Enantiomer–enantiomer interaction of ifosfamide in the rat

The objective of this study was to study the enantiomer–enantiomer interaction of ifosfamide (IFA) in a rat model. Following intravenous administration of individual IFA enantiomers or pseudo-racemates to male Sprague–Dawley rats, two enantiomers and their metabolites, 4-hydroxyIF (HOIF), N2-dechloroethylIF (N2D), N3-dechloroethylIF (N3D), and isophosphoramide (IPM), were quantified using gas chromatography/mass spectrometry (GC/MS) and isotope dilution techniques. In addition, the mutual inhibition in the metabolism between two stereoisomers was also investigated in vitro using rat liver microsomes. Pharmacokinetic parameters were similar between (R)-IFA and (S)-IFA when individual enantiomers were intravenously administered to rats separately. However, in the rats administered with the IFA racemate, half-life, mean residence time (MRT), and area under the concentration–time curve (AUC) values of (S)-IFA were significantly increased with total body clearance (CLT) being decreased. No significant difference in volumes of distribution (Vss), and renal clearance (CLr) and blood cell partition was observed between two enantiomers regardless of (R)-IFA and (S)-IFA being administered separately or in combination as a racemate. The results from the in vitro metabolism and inhibition experiment suggested that each IFA enantiomer inhibited the metabolism of its antipode in a competitive manner. It is concluded that the enantiomeric interaction of IFA mainly occurred in the process of metabolism with (S)-IFA being affected to a larger extent.

Enantiomeric interactions between nucleic acid bases and amino acids on solid surfaces.

Molecular interaction between nucleic acid bases and amino acids is a fundamental process in biology. The adsorption of the molecules on surfaces provides the opportunity to study such interactions in great detail by exploiting the high-resolution imaging capabilities of scanning tunnelling microscopy (STM). The chemisorption of prochiral molecules, such as adenine, on a metal surface causes the adsorbed species to become chiral. Subsequent interactions with inherently chiral molecules may then lead to the formation of diastereoisomers, if the enantiomeric interaction process is sufficiently strong. In the case of adenine adsorption on Cu[110], the chiral adsorbates form homochiral chains. Here, we show that the adenine chain direction is fully correlated with the chirality, and that the alpha-amino acid, phenylglycine, shows a strong chiral preference in its interaction with these chains. STM images clearly demonstrate that S-phenylglycine (R-phenylglycine) binds only to chains rotated 19.5 degrees (anti-) clockwise from the [001] direction. Closer examination reveals that the enantiomeric interaction involves double rows of phenylglycine molecules and the adenine chains. This is the first observation at the molecular level of diastereoisomeric interaction, and demonstrates that STM is a powerful method for studying the details of these interactions.

Evidence for chiral discrimination of ruthenium(ii) polypyridyl complexes by DNAElectronic supplementary information (ESI) available: absorption spectra. See http://www.rsc.org/suppdata/dt/b2/b208147d/

Here we report on the synthesis and enantiomeric resolution of metal complexes of the type [Ru(bpyMe2)2L]2+ (where bpyMe2 = 4,4′-dimethyl-2,2′-bipyridine and L = 1,10-phenanthroline (phen), dipyrido[3,2-a:2′3′-c]quinoxaline (dpq), dipyrido[3,2-a:2′3′-c](6,7,8,9-tetrahydro)phenazine (dpqc) or dipyrido[3,2-a:2′3′-c]phenazine (dppz)). DNA-paper chromatography, absorption spectroscopy, gel electrophoresis and viscometry of linear DNA were used to assess the association and affinity for DNA of the aforementioned complexes. Optical resolution of the complexes was achieved by solvent recycled chromatography using Sephadex cation exchange resin and disodium (−)-O,O′-dibenzoyl-L-tartrate. Paper chromatography successfully elucidated the relative binding affinities of the metal complexes investigated in the following order phen (0.68) < dpq (0.36) < dpqc (0.14) < dppz (0.09). Absorption spectroscopy experiments indicated that each of the complexes were in close association with the DNA. Electrophoresis of the plasmid DNA incubated with the Δ complexes of dppz or dpqc show unwinding. The Λ-isomer of dppz resulted in smearing due to less effective binding whereas the Λ-isomer of dpqc showed no unwinding at all. Unexpectedly, rac-[Ru(bpyMe2)2(dpq)]2+ showed greater unwinding than either isomer. DNA-viscosity experiments provided evidence that both the Δ and Λ-isomers of dppz and dpqc bind by intercalation. However, Δ and Λ-[Ru(bpyMe2)2(dpq)]2+ bind through different modes, the Δ isomer by intercalation and the Λ isomer by partial intercalation. The conclusions that can be drawn from this is that the extended methyl groups in the 4- and 4′-positions on the bpyMe2 ligand are critical in eliciting different enantiomeric interactions with the walls of the DNA grooves.

13C NMR spectroscopic analysis on the chiral discrimination of N-acetylphenylalanine, catechin and propranolol induced by cyclic-(1→2)-β- d-glucans (cyclosophoraoses)

Cyclosophoraoses (cyclic-(1→2)-β- d-glucans) produced by Rhizobium meliloti were used as a novel chiral NMR solvating agent. 13C NMR spectroscopic analysis as an enantiodiscriminating tool was carried out where NMR signal splittings were observed on the interactions of cyclosophoraoses with the enantiomers of N-acetylphenylalanine, catechin and propranolol. The 13C chemical shifts of cyclosophoraoses induced by the enantiomeric interactions predominantly occurred at the C-1 and C-2 carbons associated with the -glycosidic linkage.

Chiral pharmacokinetics and inversion of enantiomers of a new quinoxaline topoisomerase IIbeta poison in the rat.

XK469 (NSC 697887; (+/-)-2-[4-(7-chloro-2-quinoxaliny)oxy]phenoxy propionic acid), an analog of the herbicide Assure, which possesses antitumor activity, especially against murine solid tumors and human xenografts, has recently been found to be the first topoisomerase IIbeta poison. Both R(+) and S(-) isomers are cytotoxic, although the R-isomer is more potent. Using a chiral high-performance liquid chromatography assay, pharmacokinetics of R(+)-, S(-)-, and (+/-)-XK469 in Fischer-344 rats were investigated following their separate i.v. administrations. S(-)-XK469 was found to be predominantly converted to the R-isomer in circulation when the S-isomer was administered either alone or as a racemic mixture. No trace of the S-isomer was found in circulation or in urine or feces, following the R-isomer administration, up to 72 h. In the rat, the plasma concentration-time profiles for both isomers follow a two-compartment pharmacokinetics with the mean t(1/2beta) for the R-isomer of 24.7 h being significantly longer than 4.2 h, the mean t(1/2beta) for the S-isomer. The mean total clearance of the S-isomer was over 200-fold more rapid than that of the R-isomer, and the major clearance route of the S-enantiomer was inversion to its antipode, as estimated by the fractional formation clearance of R(+)-XK469 of 0.93. Protein binding for both enantiomers was in the range of 95 to 98%. Urinary and fecal elimination in 72 h as the intact drug were 7 to 10% and 8% of the administered dose, respectively, either administered as the individual enantiomers or as a racemate. Cumulative biliary elimination in 7 h was about 3% of the dose. No evidence of enantiomeric interaction at the pharmacokinetic level was detected.

Evaluation of quantitative structure property relationships necessary for enantioresolution with lambda- and sulfobutylether lambda-carrageenan in capillary electrophoresis.

Lambda-carrageenan, a linear, high molecular weight sulfated polysaccharide, was successfully employed in both its native and sulfobutyl derivatized form as a chiral selector in capillary electrophoresis for the separation of enantiomers of basic pharmaceutical compounds. In order to characterize the chiral selectivity properties of this chiral selector, various structurally related racemic compounds were analyzed for enantiomeric interactions using capillary electrophoresis. The results of these studies were then rationalized and analyzed utilizing a general quantitative structure-property relationship (QSPR) evaluation in order to predict critical analyte structural requirements for successful enantiomeric separation. Important structural components of the analytes were found to include the aromatic content, the type of substitution on the aromatic ring, presence of a primary or secondary protonated amine, and an overall positive charge to the molecule.

Role of cytochrome P450 2C9 and an allelic variant in the 4′-hydroxylation of ( R)- and ( S)-flurbiprofen

Flurbiprofen is a chiral non-steroidal anti-inflammatory drug used in the treatment of pain or inflammation. The primary routes of biotransformation for ( R)- and ( S)-flurbiprofen are oxidation (presumably cytochrome P450) and conjugation. To date, the specific cytochrome P450 (P450) involved in the oxidative metabolism of this compound (specifically 4′-hydroxylation) has not been elucidated. Experiments were conducted to characterize the kinetic parameters ( K m and V max) for the 4′-hydroxylation of ( R)- and ( S)-flurbiprofen in human liver microsomes, to determine if enantiomeric interactions occur when both enantiomers are present, and to identify the specific P450 form(s) involved in this reaction. In human liver microsomes, the K m and V max(mean ± SD) for ( R)-4′-hydroxy-flurbiprofen formation were 3.1 ± 0.8 μM and 305 ± 168 pmol · min −1· mg protein) −1, respectively. In comparison, the K m and V max (mean ± SD) for( S)-4′-hydroxy-flurbiprofen formation were 1.9 ± 0.4 μM and 343 ± 196 pmol · min −1 · mg protein −1, respectively. Enantiomeric interaction studies revealed a decrease in K m and V max for both enantiomers and an apparent loss of stereoselectivity. Racemic-warfarin, tolbutamide, α-naphthoflavone and erythromycin were studied as potential inhibitors of this process. The estimated K i values for the inhibition of ( R)- and ( S)-4′-hydroxy-flurbiprofen formation by racemic-warfarin were 2.2 and 4.7 μM. This reaction was also inhibited by tolbutamide. In contrast, erythromycin and α-naphthoflavone had no appreciable effect on 4′-hydroxy-flurbiprofen formation. cDNA expression of individual forms was used to determine which P450 was involved in 4′-hydroxy-flurbiprofen formation. P450 2C9 and an allelic variant (R144C) readily catalyzed the formation of 4′-hydroxy-flurbiprofen. P450 1A2 was also active albeit with a turnover rate 1 140 th that of P450 2C9R144C (P450s 2C8, 2E1 and 3A4 were not active toward either enantiomer). The results of these studies indicate that the enantiomers of flurbiprofen may exhibit stereoselectivity with respect to enzyme affinity but have roughly equal maximum formation velocities. Additionally, these two enantiomers may compete for the enzyme resulting in lower maximum velocities for both enantiomers. Finally, of those P450 forms examined, only P450 2C9 and an allelic variant catalyzed the 4′-hydroxylation of both ( R)- and ( S)-flurbiprofen.

Stereospecific evaluation of sotalol pharmacokinetics in a rat model: Evidence suggesting an enantiomeric interaction

Sotalol (STL) is a chiral beta-adrenergic blocking drug, which is useful clinically as the racemate in treating hypertension, and is also useful as a class III antiarrhythmic when administered as the pure S-enantiomer. Utilizing a stereospecific high-performance liquid chromatographic (HPLC) assay, the enantiomeric disposition of STL is reported after administration of racemate and both pure enantiomers to a rat model. After administration of the racemate, enantiomers of STL had similar plasma concentration-time profiles. Following administration of the pure S-enantiomer of STL, however, systemic clearance was significantly reduced; R-STL disposition after pure enantiomer administration was not significantly altered. Changes in systemic clearance of S-STL after either racemate or enantiomer dosing were explained by corresponding changes in renal clearance. Renal clearance values of S-STL were significantly reduced from 33.7 +/- 6.0 to 28.9 +/- 5.6 ml min-1 kg-1 for administration as racemate and pure enantiomer, respectively. As clearance of STL approximates reported values of renal blood flow, renal perfusion changes caused by the beta-blocking effects of R-STL may explain changes in S-STL disposition. It is suggested that dosing of STL as either racemate or pure enantiomer, depending on the clinical indication for use, may result in significantly altered enantiomer disposition.

Disposition kinetics of ML‐1035 sulfoxide enantiomers and the prochiral sulfide in rats

ML-1035, 4-amino-5-chloro-2-[2-(methylsulfinyl)ethoxy]-N-[2- (diethyl-amino)ethyl]benzamide, is a sulfoxide compound and a racemic gastroprokinetic agent with a chiral center at the sulfur atom. We have investigated the disposition kinetics of (R)-ML-1035 sulfoxide (R) and (S)-ML-1035 sulfoxide (S) after the single enantiomers and the racemic mixture were administered to rats in separate experiments. There was no noticeable chiral inversion after either enantiomer dose. Both enantiomers were rapidly absorbed. After dosing with enantiomers or with the racemate, the resulting plasma concentration-time curve of R was closely parallel to that of S in both intravenous and oral experiments, suggesting that the two enantiomers have approximately the same disposition kinetics. After intravenous enantiomer doses, only S underwent conversion to sulfide, suggesting that sulfidation in the liver is enantioselective. However, the enantioselective sulfidation after intravenous dosing did not introduce a difference in the global plasma disposition profiles between R and S, since the reduction reaction is a minor metabolic process. Other metabolic reactions such as sulfonation and mono-N-desethylations were not enantioselective. After oral administration, conversion to sulfide was observed for both enationers, implicating the existence of a nonhepatic pathway in sulfidation. Administration of a prochiral sulfide dose was associated with an enantioselective sulfoxidation, in which the R/S concentration ratios increased as a function of time. In addition, enatiomeric interaction causing changes in pharmacokinetic parameters was observed after the oral racemate dose, while the interaction is negligible after an intravenous racemate dose, indicating a route dependency in enantiomeric interaction.

Metabolic enantiomeric interactions: The inhibition of human (S)‐warfarin‐7‐hydroxylase by (R)‐warfarin

Inhibition of the metabolism of (S)-warfarin, the more pharmacologically active enantiomer of the racemic drug, by (R)-warfarin was investigated in microsomes obtained from three human livers. In each case the production of both (S)-6- and (S)-7-hydroxywarfarin was found to be competitively inhibited by (R)-warfarin. The KiS for inhibition of (S)-6- and (S)-7-hydroxylation by (R)-warfarin ranged from 7.0 to 8.4 microM and from 6.0 to 6.9 microM, respectively, while the KmS for the 6- and 7-hydroxylation of (S)-warfarin ranged from 3.6 to 3.8 microM and from 3.3 to 3.9 microM, respectively. In contrast, except for the 4'-hydroxylation pathway (S)-warfarin was found to be a weak inhibitor of the metabolism of (R)-warfarin. Possible implications of these findings include the following: (1) the kinetic parameters defining the interactions of two enantiomers of a racemic drug with the cytochrome P-450s or other macromolecular systems in the living organism can only be properly defined from experiments with the pure enantiomers, (2) an enantiomer of a racemic drug may contribute significantly to biological effect not by its inherent activity but by altering the pharmacokinetics of the eutomer, and (3) enantiomeric interactions are not easily detected unless directly sought and may be relatively common.

Restrictive cardiomyopathy.

Rates of hydrolysis of racemic and enantiomeric lorazepam 3-acetates (LZA) by esterases in human and rat liver microsomes and rat brain S9 fraction were compared. LZA and its hydrolysis product were analyzed by chiral stationary phase HPLC. When rac-LZA was the substrate, the (R)-LZA was hydrolyzed 2.7-fold and 6.8-fold faster than the (S)-LZA by esterases in rat and human liver microsomes, respectively. In contrast, esterases in rat brain S9 fraction were enantioselective toward the (S)-LZA. The specific activities (nmol of LZA hydrolyzed/mg protein/min) of liver microsomes in the hydrolysis of enantiomerically pure (R)-LZA were approximately 210 (rat) and 1330 (human), and in the hydrolysis of enantiomerically pure (S)-LZA were 25 (rat) and 8 (human). The specific activities of rat brain S9 fraction in the hydrolysis of enantiomerically pure (R)-LZA and (S)-LZA were approximately 3 and 6 nmol/mg protein/min, respectively. Results also indicated an enantiomeric interaction in the hydrolysis of rac-LZA; the presence of (R)-LZA stimulated the hydrolysis of (S)-LZA by all esterase preparations, whereas the presence of (S)-LZA stimulated the hydrolysis of (R)-LZA in rat brain S9 fraction and inhibited the hydrolysis of (R)-LZA in rat and human liver microsomes.