摘要:

Abstractrac‐Bupivacaine HCl was infused intravenously to constant arterial blood drug concentrations in sheep using a regimen of 4 mg/min for 15 min followed by 1 mg/min to 24 h. At 24 h, arterial blood was sampled, the animal was killed with a bolus of KCl solution, then rapidly dissected and samples were obtained from heart, brain, lung, kidney, liver, muscle, fat, gut, and rumen. Tissue:blood distribution coefficients for (+)‐(R)‐bupivacaine exceeded those of (−)‐(S)‐bupivacaine (P<0.05) for heart, brain, lung, fat, gut, and rumen by an overall mean of 43%. Blood:plasma distribution coefficients of (−)‐(S)‐bupivacaine exceeded those of (+)‐(R)‐bupivacaine by a mean of 29% and this offset the tissue:blood distribution coefficients so that the previously significant enantioselective differences disappeared. It is concluded that although enantioselectivity of bupivacame distribution is shown by the measured tissue:blood distribution coefficients, it is not shown when tissue:plasma water distribution coefficients are calculated, suggesting that there is no intrinsic difference between the bupivacaine enantiomers in tissue affinity. Sheep given fatal intravenous bolus doses ofrac‐bupivacaine had significantly greater concentrations of (+)‐(R)‐bupivacaine than (−)‐(S)‐bupivacaine in brain (P= 0.028) and ventricle (P= 0.036); these could augment the greater myocardial toxicity of this enantiomer found

ISSN:0899-0042    

DOI:10.1002/chir.530050702

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY

摘要:

AbstractThe most common, and sometimes life‐threatening, side‐effects associated with the human use of the analgesic, nonsteroidal antiinflammatory drugs (NSAIDs) are gastrointestinal. These include gastritis, ulceration, and severe bleeding. The aryl propionic acid class of NSAIDs are among the most widely used of these drugs in the world, includingrac‐ibuprofen,rac‐flurbiprofen, andrac‐ketoprofen. Marketed as racemates, it was assumed that the “inactive” (R)‐enantiomers, having no cyclooxygenase inhibiting effect, also had no toxic effect. In a 30‐day dose response study of (S)‐, (R)‐, andrac‐flurbiprofen given daily over a range of doses the (R)‐isomer alone proved to be without apparent gastrointestinal (GI) toxicity. On the other hand the racemate proved to be 2 to 4 times as ulcerogenic in enantiomerically equivalent doses as the (S)‐enantiomer. These results have significant clinical implicati

ISSN:0899-0042    

DOI:10.1002/chir.530050703

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY

摘要:

AbstractThe synthesis of the enantiomers of bupropion, (rac)‐2‐tert‐butylamino‐3′‐chloropropiophenone1(Wellbutrin®) is described. The enantiomers were compared with the racemate in both the tetrabenazine‐induced sedation model and the inhibition of uptake of biogenic amine assay. No significant differences were found in their potencies to reverse tetrabenazine‐induced sedation in mice or in their IC50values as inhibitors of biogenic amine uptake into nerve endings obtained from mouse brain. © 199

ISSN:0899-0042    

DOI:10.1002/chir.530050704

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY

摘要:

AbstractThe detoxication of the enantiomers of glycidyl 4‐nitrophenyl ether (GNPE), (−)‐(R)‐ and (+)‐(S)‐GNPE, and glycidyl 1‐naphthyl ether (GNE), (−)‐(R)‐ and (+)‐(S)‐GNE, by rat liver glutathione transferase and epoxide hydrolase was studied. Enantioselectivity was observed with both enzymes favoring the (R)‐isomers as determined by the formation of conjugate, diol, and remaining substrate measured by HPLC. Enantiomers of GNE were detoxified by cytosolic epoxide hydrolase but those of GNPE were not. Substantial nonenzymatically formed conjugates of enantiomers of GNPE were detected showing (S)‐GNPE the more reactive of the p

ISSN:0899-0042    

DOI:10.1002/chir.530050705

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY

摘要:

AbstractAn enantioselective HPLC bioassay has been developed relying on extraction of (R)‐ and (S)‐atenolol from alkalinized plasma or serum (pH>12) into dichloromethane containing 5% (v/v) 1‐butanol followed by an achiral derivatization of the drug with phosgene leading to (R)‐ and (S)‐oxazolidine‐2‐one derivatives. Under these conditions there was quantitative conversion of the acetamido group to the corresponding nitrile. These stable derivatives were separated on a (R,R)‐diaminocylohexane‐dinitrobenzoyl chiral stationary phase [(R,R)‐DACH‐DNB] using dichloromethane/methanol 98/2 as mobile phase. Determination limits of 0.5 ng for (R)‐ and 0.6 ng for (S)‐atenolol could be achieved using fluorimetric detection. The assay was applied to a human pharmacokinetic study which was performed in a randomized cross‐over, double‐blind fashion in 12 healthy volunteers, administering single oral doses of 100 mg (R,S)‐, 50 mg (R)‐, and 50 mg (S)‐atenolol AUC0–24andCmaxvalues of (R)‐atenolol were slightly but significant higher than those of (S)‐atenolol. The R/S ratios were 1.09 for AUC(R)/AUC(S) and 1.03 forCmax(R)/Cmax(S) (P<0.01) respectively after administration of the racemic drug. However, there were no differences between AUC,Cmax, andt½values of each enantiomer, whether they were administered as single enantiometers or in the form of i

ISSN:0899-0042    

DOI:10.1002/chir.530050706

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY

摘要:

AbstractOn a column with bovine serum albumin (BSA) immobilized covalently to silica, the adsorption isotherms of the enantiomers of mandelic acid, tryptophan, 2‐phenylbutyric acid, andN‐benzoylalanine are measured using a buffered mobile phase. Knowing the amount of BSA immobilized on the column (36 mg), the ratio of the number of enantiomer molecules needed to saturate the enantioselective retention mechanism to the number of BSA molecules is determined. The mean of the set of eight enantiomers is 0.28. These data confirm that at most one enantioselective site exists for each BSA molecule for the kind of enantiomers studied. © 1993 Wiley‐Lis

ISSN:0899-0042    

DOI:10.1002/chir.530050707

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY

摘要:

AbstractHigh‐performance capillary electrophoresis (HPCE) and micellar electrokinetic capillary chromatography (MECC) were applied to the resolution of racemic nonsteroidal antiaromatase drugs and intermediates. Successful results were obtained in both modes using α‐cyclodextrin (α‐CD), β‐cyclodextrin (β‐CD), γ‐cyclodextrin (γ‐CD), or 2,6‐di‐O‐methyl‐β‐cyclodextrin (DM‐β‐CD) as chiral selectors. Depending on the structure of the solute, one of the cyclodextrins was generally better suited for resolution of the racemate. The basic solutes were analyzed under HPCE conditions, whereas the nonionizable compounds such as glutethimide (Doriden®) were analyzed in MECC mode. For the azole‐type antiaromatase Fadrozole, both HPCE and MECC modes could be used to achieve the separation of the enantiomers. The influence of experimental factors such as pH, the presence of organic modifier, temperature, the micelle concentration, and the concentration of the chiral selector is also discussed on the basis of the results obtained with some chiral barbiturates. The possibility of analyzing the enantiomers directly in plasma samples was als

ISSN:0899-0042    

DOI:10.1002/chir.530050708

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY

摘要:

AbstractThe interaction mechanism of a variety of racemic alkyl aryl sulfoxides with a π‐acid HPLC stationary phase containingN,N′‐(3,5‐dinitrobenzoyl)‐trans‐1,2‐diaminocyclohexane chiral selector was investigated by means of quantum‐chemical calculations (MNDO), partial least squares (PLS) analysis, and 3D comparative molecular field analysis (CoMFA). Quantitative structure–enantioselective retention relationships (QSERR), were derived which have yielded significant insights into physicochemical properties primarily responsible for chiral recognition. The increase in retention (k′) is favored especially by the analyte π‐basic character, accounted for by the sum of the electrophilic superdelocalizabilities of all aromatic carbon atoms (SPhHOMO), and to minor extent by the H‐bond basicity of the sulfoxide oxygen and the hydrophilicity of solutes. In contrast, the separation factor (α) varied mainly with the steric properties of the substituents and with polar and electrostatic properties of the sulfoxide group. A 3D‐QSERR analysis using CoMFA methodology has provided a more complete description of factors responsible for chiral recognition and has proven to be a useful tool to examine differences in noncovalent fields (both the electrostatic and the steric) mostly associated with variations of enantioselecti

ISSN:0899-0042    

DOI:10.1002/chir.530050709

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY

摘要:

AbstractThe resolution of racemic δ‐phenyl‐δ‐valerolactone by chromatography on cellulose triacetate CTA I results in one of the best separations of optical antipodes observed so far on this chiral stationary phase. The thermodynamics of the stereoselective interaction of the enantiomers of δ‐phenly‐δ‐valerolactone have been studied by chromatography at different temperatures and by direct microcalorimetric investigations of the complexation with CTA I. This analysis suggests that the separation process is mainly controlled thermodynamically and that kinetic effects, if any, play a minor role. Microcalorimetric titration experiments indicate that specific (optimum) complexation sites on CTA I for the stronger retained enantiomer of δ‐phenly‐δ‐valerolactone are rapidly saturated, whereas the first eluted enantiomer seems to interact much less selectively with defined interaction sites on the chiral polymer matrix.

ISSN:0899-0042    

DOI:10.1002/chir.530050710

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY

摘要:

AbstractDirect enantiomeric separations of 17 chiral amidotetralins by means of high performance liquid chromatography were performed on stationary phases composed of tris(3,5‐dimethylphenylcarbamate) derivatives of cellulose and amylose, coated on silica gel. The enantiomers of 15 out of 17 amidotetralins were resolved with a resolution of more than 1.5 by at least one of the chiral stationary phases. The stationary phases showed complementary results with regard to the separation of the amidotetralins, that is, pairs that did not separate on the cellulose‐type column were well separated on the amylose‐type column, and vice versa. There was no significant correlation between the chromatographic properties of the chiral stationary phases. © 1993 Wiley‐L

ISSN:0899-0042    

DOI:10.1002/chir.530050711

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY