摘要:

AbstractNo Absract.

ISSN:0899-0042    

DOI:10.1002/chir.530020302

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

Abstract(R)‐2‐Arylpropionates are often inverted to the pharmacologically active S‐enantiomers in vivo, although there is significant interspecies variability in inversion. In order to provide a basis for determining the biochemical consequences of this unique process using rats as a model, it was important to establish the pharmacokinetic disposition of the enantiomers of ibuprofen, a drug well inverted in man and flurbiprofen, a drug apparently poorly inverted in man. Rats were dosed i.v. with a single dose of (R)‐or (S)‐ibuprofen (20 mg/kg), (R,S)‐ibuprofen (40 mg/kg), (R)‐ or (S)‐flurbiprofen (10 mg/kg), or (R,S)‐flurbiprofen (20 mg/kg). Each treatment group consisted of six animals. Serial blood samples were withdrawn over a period of 6 h for ibuprofen and 10 h for flurbiprofen. These drugs were assayed in plasma by a stereospecific HPLC assay. The pharmacokinetics of the ibuprofen and flurbiprofen enantiomers were evaluated using a two‐compartment open model with conversion of the R‐ to S‐enantiomers in the central compartment. There was 50 ± 4% inversion of (R)‐ibuprofen, a figure similar to that observed in man and (R)‐ibuprofen had a higher clearance (12.6 ± 1.3 ml/min/kg) than (S)‐ibuprofen (7.7 ± 0.7 ml/min/kg;P<0.01). The clearance of (R)‐ flurbiprofen after racemate (2.3 ± 0.1 ml/min/kg) was higher than its clearance when administered alone (1.7 ± 0.2 ml/min/kg;P<0.01), indicating a pharmacokinetic interaction between the enantiomers (most probably at plasma protein binding sites). A corresponding difference was not observed for ibuprofen. There was a small amount of inversion of (R)‐flurbiprofen as determined by area analysis (4.5 ± 1.6%). However, this calculation may be in some error because of the interaction between the enantiomers. These data demonstrate quantitative similarities in the inversion of ibuprofen and flurbiprofen in rats and man, a useful basis for comparing the effects of t

ISSN:0899-0042    

DOI:10.1002/chir.530020303

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractEnantiomeric pairs of 1‐hydroxy‐3‐hydroxymethylcholanthrene (1‐OH‐3‐OHMC), 3‐methylcholanthrene (3MC)trans‐ andcis‐1,2‐diols, and 1‐hydroxy‐3‐methylcholanthrene (1‐OH‐3MC) were resolved by HPLC using a covalently bonded (R)‐N‐(3,5‐dinitrobenzoyl)phenylglycine chiral stationary phase (Pirkle type 1A) column. The absolute configuration of an enantiomeric 3MCtrans‐1,2‐diol was established by the exciton chirality CD method following conversion to a bis‐p‐N,N‐dimethylaminobenzoate. Incubation of an enantiomeric 1‐OH‐3MC with rat liver microsomes resulted in the formation of enantiomeric 3MCtrans‐ andcis‐1,2‐diols; the absolute configurations of the enantiomeric 1‐OH‐3MC and 3MCcis‐1,2‐diol were established on the basis of the absolute configuration of an enantiomeric 3MCtrans‐1,2‐diol. Absolute configurations of enantiomeric 1‐OH‐3‐OHMC were determined by comparing their CD spectra with those of enantiomeric 1‐OH‐3MC. The relative amount of three aliphatic hydroxylation products formed by rat liver microsomal metabolism of racemic 1‐OH‐3MC was 1‐OH‐3‐OHMC>3MCcis‐1,2‐diol>3MCtrans‐1,2‐diol. Enzymatic hydroxylation at C2of racemic 1‐OH‐3MC was enantioselective toward the 1S‐enantiomer over the 1R‐enantiomer (∼3/1); hydroxylation at the C3‐methyl group was enantioselective toward the 1R‐enantiomer over the 1S‐enantiomer (∼58/42). Rat liver microsomal C2‐hydroxylation of racemic 1‐OH‐3MC resulted in a 3MCtrans

ISSN:0899-0042    

DOI:10.1002/chir.530020304

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractRates of hydrolysis of racemic and enantiomeric oxazepam 3‐acetates (OXA) by esterases in human and rat liver microsomes and rat brain S9 fraction were compared. When rac‐OXA was the substrate, esterases in human and rat liver microsomes were highly enantioselective toward (R)‐OXA. In contrast, esterases in rat brain S9 fraction were highly enantioselective toward (S)‐OXA. Hydrolysis rates of rac‐OXA were highly dependent on the amount of esterases used. At 0.05 mg protein equivalent of esterases and 150 nmol of rac‐OXA per ml of incubation mixture, the (R)‐OXA was hydrolyzed 3.6‐fold and 18.5‐fold faster than (S)‐OXA by rat and human liver microsomes, respectively. The specific activities (nmol of OXA hydrolyzed/mg microsomal protein/min) of liver microsomes in the hydrolysis of enantiomerically pure (R)‐OXA were approximately 120 (rat) and 1,980 (human), and in the hydrolysis of enantiomerically pure (S)‐OXA were 4 (rat) and 7 (human), respectively. In the incubation of rac‐OXA with rat brain S9 fraction, (S)‐OXA was hydrolyzed ∼6‐fold faster than (R)‐OXA. Results also indicated an enantiomeric interaction in the hydrolysis of rac‐OXA by esterases in rat and human liver microsomes; the presence of (R)‐OXA stimulated the hydrolysis of (S)‐OXA, whereas the presence of (S)‐OXA inhibited the hydrolysis of (R)‐OXA. In rat brain S9 fraction, the presence of (R)‐OXA inhibited the hydrolysis of (S)‐OXA, whereas the presence of (S)‐OXA appe

ISSN:0899-0042    

DOI:10.1002/chir.530020305

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractThe prochiral anthelmintic drug albendazole was administered orally to sheep and rats. Blood samples were taken at standardized intervals during the time course of the plasma kinetics: 18 h in rats and 48 h in sheep. The enantiomeric ratio of the sulfoxide metabolite was determined by means of HPLC on a chiral stationary phase, the chiral selector of which was aN‐3,5‐dinitrobenzoyl derivative of (S)‐tyrosine. Two enantiomers were detected in both animal species but their ratios were inverted in rat vs. sheep. The evolution of the ratio is turned from a racemate at 15 min to 60(−):40(+) at 12 h in rats, while it moved from 23(−):77(+) at 3 h to 4(−):96(+) at 36 h after administrati

ISSN:0899-0042    

DOI:10.1002/chir.530020306

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractThe binding of the title benzodiazepine enantiomers and its modulation by warfarin and bilirubin were studied by chromatography on human serum albumin (HSA) immobilized on Sepharose 4B, and also by a combination of ultrafiltration and circular dichroism (UF‐CD) methods. In the absence of warfarin and bilirubin the binding of the benzodiazepine was not stereoselective. (S)‐Benzodiazepine and (S)‐warfarin mutually increased the binding of each other, while the binding of (R)‐benzodiazepine was preferentially enhanced on HSA saturated with bi

ISSN:0899-0042    

DOI:10.1002/chir.530020307

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractThe stereochemistry of an achiral (Diazepam) and two chiral (3‐methyl and 3‐succinyloxy substituted) 1,4‐benzodiazepin‐2‐ones interacting with human serum albumin (HSA) has been investigated by making use of difference absorption (UV) and circular dichroism (CD) spectroscopies. Evidence is obtained for a higher affinity with HSA for one of the two possible conformations of the seven‐membered benzodiazepine ring. The red shift revealed by the absorption difference spectrum between the free and the bound drug accounts for the CD difference spect

ISSN:0899-0042    

DOI:10.1002/chir.530020308

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractFrom a study of the13C‐shift values of the MTPA esters of 3‐substituted cyclohexanols of known absolute configuration an empirical rule has been developed to determine the absolute configuration of chiral cyclohexanols. The method is based on the Dale–Mosher model, which was originally developed for1H‐NMR spectra. The scope and limitations of this method are discussed. The enantiomeric purity of the alcohols can be determined simultaneously by integration of the signals in well‐resolved diastereotopic car

ISSN:0899-0042    

DOI:10.1002/chir.530020309

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

Abstract(R,S)‐N‐Acetyl‐leucine‐2‐naphthylamide can be resolved into its enantiomers on a (S)‐DNBLeucine chiral stationary phase. The mechanism of this separation was investigated using as model complexes the 1:1 S,S‐ and the 1:1 R,S‐cocrystals of the above naphthylamide andN‐3,5‐dinitrobenzoylleucinemethylamide, a soluble analogue of the stationary phase. The observed enantiomeric elution order can be rationalized fr

ISSN:0899-0042    

DOI:10.1002/chir.530020310

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractA study developing enantiomeric separations by metal chelate additives to the mobile phase in reversed‐phase liquid chromatography is reported. In particular the use of Cu(II) complexes of L‐prolinamide (L‐ProNH2) and L‐valinamide (L‐ValNH2) is examined and discussed. Interestingly, for a series of DNS‐amino acids these selectors show higher enantioselectivity than that obtained with the corresponding nonderivatized amino acid–Cu(

ISSN:0899-0042    

DOI:10.1002/chir.530020311

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY