摘要:

AbstractAs an experimental model for reduced liver function rats with surgical portacaval shunts (pcs) may be used. Carvedilol, a nonselective β‐adrenoceptor antagonist with vasodilating activity, is extensively metabolised by phase I as well as phase II pathways. In order to study the stereoselective pharmacokinetics of carvedilol in liver disease, pcs and control rats were given rac‐carvedilol intravenously and p.o. The carvedilol enantiomers and their conjugates were assayed in plasma, urine, and bile. Carvedilol was highly bound to plasma proteins; binding was reduced by pcs. In all groups, the plasma concentrations of (R)‐carvedilol exceeded those of (S)‐carvedilol significantly. In comparison to the control group the plasma concentrations of both enantiomers increased after pcs, while the difference between the stereoisomers decreased. The total clearance decreased proportionally to the decrease in liver weight (30%). Both the apparent oral clearance, as well as its stereoselectivity were reduced, by up to 90 and 43%, respectively. The biliary clearance of the parent drug after i.v. dosage increased in rats with pcs due to the reduced hepatic metabolism. © 1993 Wiley

ISSN:0899-0042    

DOI:10.1002/chir.530050102

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY

摘要:

AbstractThe effects of (±)‐, (+)‐, and (−)‐atenolol, sotalol, and amosulalol alone on the rat left atria and portal vein and on the respective β1‐ and β2‐adrenoceptor‐mediated responses to isoprenaline have been determined. (±)‐Atenolol at 10−6Mhad no effect whereas high concentrations of (+)‐ and (−)‐sotalol, 10−5–10−4M, and (±)‐, (+)‐, and (−)‐amosulalol depressed the response of the rat left atria to cardiac stimulation which indicates membrane stabilizing activity. None of the drugs tested had any effect alone on the rat portal vein. The order of potency as antagonists was (±)‐amosulalol>(±)‐atenolol>(±)‐sotalol at β1‐adrenoceptors and (±)‐amosulalol>(±)‐sotalol>(±)‐atenolol at β2‐adrenoceptors. (±)‐Atenolol and (±)‐amosulalol are β1‐selective whereas (±)‐sotalol is β2‐selective. For each of the racemic β‐blockers, the β1‐ and β2‐adrenoce

ISSN:0899-0042    

DOI:10.1002/chir.530050103

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY

摘要:

AbstractIn a randomized, double‐blind, cross‐over study in 12 healthy volunteers, the effects of single oral doses of 100 mg rac‐atenolol were compared during exercise to those of equal amounts of the optically pure enantiomers, i.e., 50 mg (R)‐ and 50 mg (S)‐atenolol. The mean rate pressure product decreased with rac‐atenolol (−37%;P<0.01) and half‐dosed (S)‐atenolol (−35%;P<0.01) to the same extent, whereas (R)‐atenolol caused no effect. Radioligand binding studies in beta‐adrenergic receptors of the guinea pig heart yielded a eudismic ratio of 46 for (S)‐ to (R)‐atenolol. The mean AUCs, maximal plasma concentrations, and plasma half‐lives of the enantiomers were similar regardless of whether they were administered as optically pure enantiomers or as racemic mixture. On the other hand, the AUC of (R)‐atenolol was 1.08‐fold greater (P<0.01) than that of the (S)‐enantiomer. The reason for this finding remains unclear. We conclude that only (S)‐atenolol, but not (R)‐atenolol, contributes to the beta‐blocking effect of currently used rac‐atenolol since the same effect can be elicited with the (

ISSN:0899-0042    

DOI:10.1002/chir.530050104

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY

摘要:

AbstractThe absolute configuration of (+)‐cis‐2,3‐dihydro‐2[(methylamino)methyl]‐1‐[4‐(trifluoromethyl)pheno

ISSN:0899-0042    

DOI:10.1002/chir.530050105

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY

摘要:

AbstractIn the present paper, a study on the stereoselectivity of 25 lipases of animal and microbial origin towards homogeneous prochiral triglycerides is presented. All the lipases tested catalyse the hydrolysis of the chemically alike but sterically nonequivalent ester groups in trioctanoin and triolein with different degrees of stereobias, depending on the fatty acyl chain length of the substrate (Rogalska et al., J. Biol. Chem. 256:20271–20276, 1990). Hydrolysis of thesn‐2 ester group is catalysed by very few lipases and onlyCandida antarcticaA shows a clear preference for this position. Most of the lipases investigated (12 with trioctanoin and 16 with triolein) showed a preference for thesn‐1 position. Using trioctanoin as substrate we observed a total stereoselectivity for positionsn‐1 withPseudomonassp. andPseudomonas aeruginosaand for positionsn‐3 withCandida antarcticaB. This was not the case with triolein as substrate. Among the 23 lipases studied here and the other two lipases described previously (Rogalska et al., J. Biol. Chem. 256:20271–20276, 1990), 17 show a higher stereoselectivity with trioctanoin than with triolein. With guinea pig pancreatic lipase and with three mold lipases (Geotrichum candidumM,Geotrichum candidumA, andCandida antarcticaB), the preference switches fromsn‐3 tosn‐1 when the acyl chain length increases from eight to 18 carbon atoms. The main conclusion to emerge from the present study is that the specific stereopreference of each lipase for a given substrate under given lipolytic conditions can be said to be its fingerprint. © 1993

ISSN:0899-0042    

DOI:10.1002/chir.530050106

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY

摘要:

AbstractA high‐performance liquid chromatographic (HPLC) analytical method is described for the quantification of the (R)‐ and (S)‐enantiomers of ketorolac when present together in human plasma. The method involves derivatization with thionyl chloride/(S)‐1‐phenylethylamine and subsequent reversed‐phase chromatography of the diastereomeric (S)‐1‐phenylethylamides of (R)‐ and (S)‐ketorolac. The method is suitable for the analysis of large numbers of plasma samples and has been applied in this report to a pharmacokinetic study of ketorolac enantiomers upon intramuscular administration of racemic drug to a human subject. The limit of quantification for each enantiomer of ketorolac is 50 ng/ml (signal‐to‐noise ratio>10).

ISSN:0899-0042    

DOI:10.1002/chir.530050107

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY

摘要:

AbstractThe enantiomeric resolution of six closely related hexa‐ and octa‐hydrobenzo(g) quinoline racemates by HPLC on an ovomucoid column (Ultron ES‐OVM) is described. First, the influence of uncharged mobile phase additives (with different hydrogen bonding properties) and pH on retention and enantioselectivity is investigated. It is shown that an optimum pH of around 6 for the given separations is much more important than the choice of modifier. Second, the influence on enantioselectivity of small differences in molecular structure is examined. In one case a large difference is obtained for diastereomeric racemates depending on the cis‐ or trans‐configuration of the quinoline skeleton. Higher flexibility of the solute seen in the cis enantiomers seems to improve enantioselectivity. © 1993 Wiley

ISSN:0899-0042    

DOI:10.1002/chir.530050108

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY

摘要:

AbstractAn asymmetric transformation of racemict‐butyl 2‐(3,4‐O‐carbonyldioxy‐phenyl)‐2‐(phthalimidooxy)acetate [(RS)‐2b] into one of its optically active forms was carried out by a combination of preferential crystallization of a desired enantiomer and the simultaneous racemization of the antipode. (R)‐2bwas easily racemized in diethylketone in the presence of a small amount of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU). Under the conditions for racemization, the asymmetric transformation was achieved successfully to give (S)‐2bwith 84% optical purity in 80% yield. A potent antipseudomonal cephalosporin M‐14659 (1) was prepared from the pure (S)‐2bwhich was obtained by the recrystallization of the crude (

ISSN:0899-0042    

DOI:10.1002/chir.530050109

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY

ISSN:0899-0042    

DOI:10.1002/chir.530050110

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY

ISSN:0899-0042    

DOI:10.1002/chir.530050101

出版商:Alan R. Liss, Inc.    

年代:1993

数据来源: WILEY