摘要:

AbstractThe effects of the enantiomers of ibuprofen (0.25 and 0.50 mmol/kg b.w.) and flurbiprofen (0.01, 0.03, and 0.06 mmol/kg b.w.) on the β‐oxidation of palmitate were investigated in the rat. The mean cumulative exhalation of14CO2after ip administration of [U‐14C]palmitic acid was significantly reduced over 6 h by ibuprofen at the higher dose but not at the lower dose for either enantiomer. There was no difference between the enantiomers, the reduction over 6 h being 31.3 and 33.0% for (R)‐ and (S)‐ibuprofen, respectively. There was also a significant inhibition of β‐oxidation by flurbiprofen at all 3 doses. Again, there was no stereoselectivity evident in this inhibition. Flurbiprofen was much more potent than ibuprofen in eliciting this effect, the 0.01mmol/kg dose giving a similar reduction in β‐oxidation as observed for the 0.50 mmol/kg dose of ibuprofen. The data support the hypothesis that inhibition of the in vivo β‐oxidation of palmitate by ibuprofen and flurbiprofen is primarily via a nonstereoselective noncoenzyme A‐dependent mechanism. ©

ISSN:0899-0042    

DOI:10.1002/chir.530040302

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY

摘要:

AbstractRacemic ethotoin (1000 mg) was administered orally as a single dose to six healthy adult volunteers. Blood samples were collected at appropriate times for 120 h following the dose. Ethotoin was quantified enantioselectively in plasma using a novel chiral column HPLC procedure. One of the enantiomers of the chiral metabolite, 5‐phenylhydantoin, was also quantified in the HPLC method. TheCmaxand AUC0—∞values for (+)‐(S)‐ethotoin were significantly greater than those for (—)‐(R)‐ethotoin (ratio of mean AUC0—∞values 0.88), but the elimination half‐lives of the isomers were virtually identical [12.35 ± 5.15 h for (—)‐(R)‐thotoin; 12.28 ± 5.34 h for (+)‐(S)‐ethotoin]. Parameters derived from AUC0—∞(Cl0/FandVarea/F) also differed slightly between the isomers. The data were interpreted as indicating a small difference in the absorption of the two isomers; it seemed unlikely, in terms of the identical elimination rates, that their metabolic profiles would differ greatly. The 5‐phenyl‐hydantoin was eliminated with a significantly longer half‐life (18.69 ± 6.11 h) than that of ethotoin. Enantioselectivity in the pharmacokinetics of ethotoin is the

ISSN:0899-0042    

DOI:10.1002/chir.530040303

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY

摘要:

AbstractAfter intravenous bolus injection ofrac‐carvedilol at 2 mg/kg to the rat, the (+)‐(R)‐ and (—)‐(S)‐enantiomer levels in the blood and tissues (liver, kidney, heart, muscle, spleen, and aorta) were measured by stereospecific HPLC assay. As compared with the (+)‐(R), the (—)‐(S) had a larger Vdss(3.32 vs. 2.21 liter/kg), MRT (33.4 vs. 25.6 min), and CLtot(96.1 vs. 83.8 ml/min/kg). AUC comparison after iv and po administration showed systemic bioavailability of the (—)‐(S) to be about half that of its antipode, explained by the fact that the free fraction of the (—)‐(S) in blood was 1.65‐fold greater than that of the (+)‐(R). Tissue‐to‐blood partition coefficient values for the (—)‐(S) were 1.6‐ to 2.1‐fold greater than those for the (+)‐(R) in all tissues, showing that the (—)‐(S) accumulates more extensively in the tissues. These results were consistent with the greater Vdssfor the (—)‐(S) estimated from systemic blood data. The stereoselective tissue distribution of carvedilol enantiomers results from an enantiomeric difference in plasma protein binding ra

ISSN:0899-0042    

DOI:10.1002/chir.530040304

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY

摘要:

AbstractRac‐ML‐1035 (MDL 201,035: 4‐amino‐5‐chloro‐2‐[2‐(methylsulfinyl)ethoxy]—N‐[2‐(diethylamino)ethyl] benzamide hydrochloride) is a racemic gastroprokinetic with serotonergic (5‐hydroxytryptamine, 5‐HT) activity and a novel chiral sulfoxide substituent. Chromatographic and chemical methods have been developed to resolve the enantiomers of rac‐ML‐1035, and the absolute configuration of the (R)‐enantiomer has been determined. We also report pharmacological characterization of rac‐ML‐1035 and its respective isomers. Radioligand binding to rat cortical membranes revealed that (R)‐ML‐1035 (MDL 201,226) and (S)‐ML‐1035 (MDL 201,227) had equivalent activity at the 5‐HT3receptor. However, in isolated tissue studies including field‐stimulated guinea pig ileum, field‐stimulated rat fundic strip, and nonstimulated guinea pig ileum, (S)‐ML‐1035 was equally potent yet had greater maximal activity than (R)‐ML‐1035 in eliciting or facilitating cholinergic contractions. Thus, enantiomers of rac‐ML‐1035 can be resolved, and the relative configuration of these isomers infl

ISSN:0899-0042    

DOI:10.1002/chir.530040305

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY

摘要:

AbstractQualitative and quantitative use of polarimetry at one wavelength for detection during liquid chromatography is briefly reviewed. Acquisition of circular dichroism spectra by stopped‐flow and nonstop measurements has been further developed. Reasons are given why the angle of rotation, i.e., the polarimeter, is preferred for monochromatic use and differential absorbance, i.e., the dichrograph, for polychromatic requirements. Both methods are demonstrated by novel applications, mainly to enantiomers which interconvert thermally via intramolecular processes. © 1992 Wiley‐Liss,

ISSN:0899-0042    

DOI:10.1002/chir.530040306

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY

摘要:

AbstractThe direct HPLC separation of three chiral carbinols of general formula Mesityl‐CH(OH)‐Aryl has been achieved using Pirkle (R)‐DNBPG ionic or covalent columns and, for Aryl =o‐tolyl, on a Chiralpak OP(+) phase. It is apparent that steric hindrance and hydrogen bonding play important roles in chiral recognition. Two compounds structurally very similar but lacking the hydroxyl group were not resolved in their enantiomeric pairs. © 1992 Wiley

ISSN:0899-0042    

DOI:10.1002/chir.530040307

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY

摘要:

AbstractThe optical resolution of seven β‐blockers which have in common theN‐isopropyl‐3‐aryloxy‐2‐hydroxypropylamine moiety was carried out by HPLC using the cellulose tris(3,5‐dimethylphenylcarbamate) chiral stationary phase to quantitatively characterize the enantioselectivity of these compounds. The capacity factors and separation factors at different column temperature were determined with some qualitative trends derived. A compensation effect was observed for these compounds where there exists an approximately linear relationship between the enantiomeric differences in enthalpic and entropic energies. © 1992

ISSN:0899-0042    

DOI:10.1002/chir.530040308

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY

摘要:

AbstractThe in vitro conversion of chiral aliphatic monoalkylsubstituted oxiranes into 1,2‐diols catalyzed by epoxide hydrolase of rat liver microsomes occurs withsubstrate enantioselectivityandregioselectivity. Substrate enantioselectivityis generally low, and has the same sense, for methyloxirane, vinyloxirane, epichloro‐, and epibromohydrin. In the hydrolysis oft‐butyloxirane inhibitory effects are involved leading to a complex pattern ofenantioselectivity. All investigated monosubstituted aliphatic oxiranes are hydrolyzed with highregioselectivityby nucleophilic attack of water at the unsubstituted ring carbon atom. The enantiomeric excess of the unreacted oxirane substrates and the diol metabolites formed were determined by complexation and inclusion gas chromatography. © 1992 Wiley‐L

ISSN:0899-0042    

DOI:10.1002/chir.530040309

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY

摘要:

AbstractThe extent ofsubstrate enantioselectivityandregioselectivityof a series of aliphatic 2,3‐dialkyl‐ and trialkylsubstituted oxiranes in their in vitro epoxide‐hydrolase‐catalyzed hydrolysis depends on the size of the alkyl residues and on the substitution pattern of the oxirane ring. The enzyme‐catalyzed hydrolysis ofcis‐oxiranes, containing at least one methyl substituent, shows complete or nearly completesubstrate enantioselectivityandregioselectivitywith nucleophilic attack by water occurring with inversion of configuration at the methylsubstituted ring carbon atom of(S)‐configuration. In the hydrolysis of the isomerictrans‐oxiranes, both enantiomers are metabolized with a higher rate for the(2S;3S)‐enantiomer. The conversion of trimethyloxirane occurs with highsubstrate enantioselectivityin favor of the(S)‐enantiomer and with completeregioselectivityat the monomethylsubstituted ring carbon atom. The differentiation of the enantiotopic ring carbon atoms (product enantioselectivity) in the smallest aliphaticmeso‐oxirane,cis‐2,3‐dimethyloxirane, leads to (2R;3R)‐butane‐2,3‐diol with ee = 86%.cis‐2‐Ethyl‐3‐propyloxirane, possessing alkyl residues larger than methyl, represents an extremely poor substrate in the epoxide‐hydrolase‐catalyzed

ISSN:0899-0042    

DOI:10.1002/chir.530040310

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY

摘要:

AbstractSeveral α‐monoalkyl‐α‐aryloxyacetic acids have been synthesized and resolved into their optical antipodes; their absolute configuration was also established by chiroptical and chemical methods. The two enantiomers of a series of these compounds show opposite effects on skeletal muscle fibers chloride conductance. Therefore a HPLC procedure was developed for the direct determination of the optical purity of the antipodes before submitting them to biological tests. The chromatographic study was performed on DACH‐DNB chiral stationary phase which shows a remarkable enantioselectivity for the considered compounds as free acids, esters and amides under different conditions with essentially the same chiral mechanism of separation. © 1992 Wiley

ISSN:0899-0042    

DOI:10.1002/chir.530040311

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY