Effects of Protein Binding on the Isomerization of Ceftibuten

Shimada, Jingoro; Hori, Seiji; Oguma, Takayoshi; Yoshikawa, Tomohiro; Yamamoto, Sachiko; Nishikawa, Takashi; Yamada, Hideo

doi:10.1002/jps.2600820506

Cited by 15 publications

(8 citation statements)

References 18 publications

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“…Similar acceleration of inversion (racemization or epimerization) in plasma and albumin solutions has been reported for thalidomide, 12 ceftibuten, 11 carbenicillin, 9 ethiazide, 9 and tolperison. 9 In the case of thalidomide, racemization was accelerated fourfold to ®vefold in HSA and human plasma and 25±31-fold in buer.…”

Section: Discussionsupporting

confidence: 74%

“…9 In the case of thalidomide, racemization was accelerated fourfold to ®vefold in HSA and human plasma and 25±31-fold in buer. 12 The stereoselectivity of epimerization at the 5 position of the thiazolidine ring exhibits a 1´3±1´5-fold dierence between the 2S-and 2R-isomers (Table 1), and is lower than that for ceftibuten, 2´5-fold, between the cis-and trans-isomers in human serum 11 and similar to the thalidomide 1´4-fold dierence between the (+) and (7) isomers in human citrated plasma. 12 The reason for this acceleration may be that epimerization occurs by base attack on the proton at the 5 position of the thiazolidine ring.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetic Stereoselectivity of Troglitazone, an Antidiabetic Agent, in the Kk Mouse

Izumi

Enomoto

Hoshiyama

et al. 1997

Biopharm. Drug Dispos.

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Troglitazone, an oral antidiabetic agent, is an equal mixture of four stereoisomers involving two asymmetric centres. In the present study, the stereoselectivity of in vitro epimerization in plasma and organ homogenate and in vivo plasma disposition in the KK mouse, an animal model of non‐insulin‐dependent diabetes, was examined. In the incubation experiments at 37 °C, there was a fivefold to eightfold acceleration of epimerization at the 5 position of the thiazolidine ring in KK mouse plasma compared with that in buffer. However, no inversion at the 2 position of the chroman ring was observed. In addition, there was an approximately 1·3‐fold difference in the epimerization rates among stereoisomers at the 2 position of the chroman ring. However, there were no differences in the values of the equilibrium constants of epimerization, and the ratio of epimerization among stereoisomers at the 5 position of thiazolidine ring was almost unity. The acceleration of epimerization is thought to be due to the high degree of protein binding because of the relationship between the initial epimerization rate and the dilution ratio of the plasma. Although acceleration of epimerization was also observed in the 20% homogenates of liver, kidney, and intestine of the KK mouse, the degree of stereoselectivity was lower than in plasma. The analysis of the plasma disposition after intravenous administration of troglitazone stereoisomers, using a kinetic model, indicated that the metabolic clearance in the liver showed a 2·5‐fold maximum difference among stereoisomers and that the stereoselectivity of epimerization was low. ©1997 by John Wiley & Sons, Ltd.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Stereoselectivity of Troglitazone, an Antidiabetic Agent, in the Kk Mouse

Izumi

Enomoto

Hoshiyama

et al. 1997

Biopharm. Drug Dispos.

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“…In addition to recovery, the stability of the enantiomers was tested using the described sample preparation procedure, since some chiral molecules will racemize at physiological or acidic pH, while others will do so at increasing pH or temperature 21, 22. In order to investigate whether or not the pindolol enantiomers interconvert during the sample preparation process, pure S ‐(−)‐pindolol was fortified into control human plasma (final concentration 200 ng/mL) and the samples were processed as described above.…”

Section: Resultsmentioning

confidence: 99%

Enantiomeric separation and quantification of pindolol in human plasma by chiral liquid chromatography/tandem mass spectrometry using staggered injection with a CTC Trio Valve system

Wang

Shen

2005

Rapid Comm Mass Spectrometry

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Pindolol is a non-selective beta-adrenergic antagonist (beta-blocker) for the treatment of cardiovascular diseases such as hypertension and angina pectoris. It has one chiral center, and, therefore, two optical isomers. It was essential to develop an enantioselective assay to measure each enantiomer in human plasma. However, separation of enantiomers using chiral chromatography usually requires relatively long retention times. This can pose a problem for rapid turnaround of a large number of samples (i.e., clinical studies). In the present study, a simple and sensitive chiral liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method was developed and validated for the determination of S-(-)- and R-(+)-pindolol in human plasma. To increase throughput, staggered sample injection was employed using a CTC Trio Valve system on a CTC HTS PAL autosampler. The method exhibited good intra- and inter-day accuracy and precision, and was linear over a dynamic range of 250 pg/mL to 250 ng/mL for each pindolol enantiomer. Intra- and inter-day accuracy ranged between 90.0-106% and 91.6-104% for both quality control (QC) samples of S-(-)- and R-(+)-pindolol, respectively. The respective intra- and inter-day precision ranged between 4.24-7.86% and 4.98-10.4%.

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“…Given proper conditions, no stereoisomer is configurationally stable [12]. Some molecules will racemize at physiological or acidic pH, while others will do so at increasing pH or temperature [13][14][15].…”

Section: Stability In Sample Preparation Proceduresmentioning

confidence: 98%