Stereoselectivity in clinical pharmacokinetics and drug development

Campbell, David B.

doi:10.1007/bf03190194

Cited by 70 publications

(36 citation statements)

References 95 publications

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“…the regulatory agencies have placed emphasis on the safety and efficacy of stereoisomers in drug development (Birkctt, 1989;Campbell, 1990;Shindo and Caldwell, 1991). In order to characterize the individual enantiomers with respect to pharmacokinetics, metabolism, pharmacology and toxicology for optimal therapeutic use, there is a growing need for methods of separating and quantitating drug enantiomers in biological fluids.…”

Section: Introductionmentioning

confidence: 99%

Gas chromatographic determination of enantiomers as diastereomers following pre‐column derivatization and applications to pharmacokinetic studies: A review

Srinivas

Shyu

Barbhaiya

1995

Biomedical Chromatography

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The introduction of chiral chromatographic methods has revolutionized the art of separation and quantitation of chiral drugs in biological fluids. A large number of chiral derivatization reagents for various functional groups are available commercially. Therefore, pre-column derivatization methods have become attractive and simple for the gas chromatographic assays in biological fluids. The intent of this article is to review the pre-column chiral derivatization reagents employed in gas chromatographic separations and analyses of enantiomers. A discussion of numerous procedures necessary to develop a quantitative gas chromatographic assay method for drug enantiomers is presented. In this regard, quantitative gas chromatographic assays based on this approach have been applied to investigate the stereoselective pharmacokinetics of several chiral drugs such as fenfluramine, norfenfluramine, methylphenidate, etodolac, propranolol, suprofen and methoxyphenamine.

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Section: Introductionmentioning

confidence: 99%

Gas chromatographic determination of enantiomers as diastereomers following pre‐column derivatization and applications to pharmacokinetic studies: A review

Srinivas

Shyu

Barbhaiya

1995

Biomedical Chromatography

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“…Drug enantiomers may exhibit biologically distinct interactions with biological systems and consequently exhibit different pharmaceutical or toxicological effects [1][2][3]. Thus, the separation and quantitative determination of enantiomers in pharmaceutical drugs is needed both during drug development and as a part of quality control.…”

Section: Introductionmentioning

confidence: 99%

Investigation of a dual CD chiral CE system for separation of glitazone compounds

Jamali¹,

Bjørnsdottir

Cornett

et al. 2009

Electrophoresis

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A dual CD-CE method for chiral separation of enantiomers of pioglitazone, rosiglitazone and balaglitazone was investigated for the purpose of optimizing the chiral separation. In a previous work a dual CD chiral CE method was used for investigation of glitazone compounds in drug substance and pharmaceutical formulation and the studies showed that all studied glitazones were racemic mixtures. This CE method could separate the enantiomers with a resolution (R(S)) of about 3. However, another study on single glitazone enantiomers pointed out that a higher R(S) is needed to achieve more accurate results for separation of a small amount of one enantiomer in the presence of a high amount of the other enantiomers. The focus of this investigation was thus directed toward the effect of CDs and the pH of the running buffer to achieve a better enantioseparation. Initially CE systems with each of heptakis(2,6-di-O-methyl)-beta-CD (DM-beta-CD) and heptakis(6-sulfobutylether)-beta-CD (SB-beta-CD) as single CD added were investigated at three different pH values (2.5, 5.0 and 9.3). After having chosen the best of these three pH values a dual CD system was further investigated and optimized. The optimization work was then focused on the concentration of the two CDs and the pH of the running buffer and was performed using factorial design experiments. A mixture of a DM-beta-CD and SB-beta-CD was found to be optimal and necessary to achieve enantioseparation with sufficiently high R(S). In order to further verify the importance of the SB-beta-CD, a CE system with the DM-beta-CD added and substitution or partial substitution of the SB-beta-CD by SDS was studied for comparison. (1)H-NMR studies were performed to get a more detailed understanding of the interactions between the glitazones and the CDs used.The optimized dual CD-CE method for chiral separation of the enantiomers of pioglitazone, rosiglitazone and balaglitazone using a running buffer containing 50 mM borate buffer pH 9.7, 12 mM of SB-beta-CD and 3 mM of DM-beta-CD provided a high R(S) (R(S) between 5.5 and 8.8).

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“…Such enantiospecific bioassays are important tools for the study of the mechanisms of action of chiral drugs. At present, the significance of stereochemistry in both the pharmacodynamic action of drugs and their pharmacokinetic fate has become increasingly important (Drayer, 1988;Campbell, 1990).…”

Section: Introductionmentioning

confidence: 99%

Rapid chiral separation of metoprolol in plasma—application to the pharmacokinetics/pharmacodynamics of metoprolol enantiomers in the conscious goat

Leloux¹

1992

Biomedical Chromatography

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The plasma concentrations of metoprolol enantiomers have been determined by means of a direct phenyl carbamate-cellulose-based chiral high performance liquid chromatography assay using fluorimetric detection. This assay has been used to investigate the pharmacokinetics and pharmacodynamics of metoprolol enantiomers in the conscious goat. There is evidence that the pharmacokinetics of metoprolol in the goat occurs stereoselectively and that enantiomer-enantiomer pharmacokinetic interactions occur. R-Metoprolol is less effective in reducing the mean arterial blood pressure than S- and R/S-metoprolol.

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Stereoselectivity in clinical pharmacokinetics and drug development

Cited by 70 publications

References 95 publications

Gas chromatographic determination of enantiomers as diastereomers following pre‐column derivatization and applications to pharmacokinetic studies: A review

Gas chromatographic determination of enantiomers as diastereomers following pre‐column derivatization and applications to pharmacokinetic studies: A review

Investigation of a dual CD chiral CE system for separation of glitazone compounds

Rapid chiral separation of metoprolol in plasma—application to the pharmacokinetics/pharmacodynamics of metoprolol enantiomers in the conscious goat

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