Direct resolution of the stereoisomers of leucovorin and 5-methyltetrahydrofolate using a bovine serum albumin high-performance liquid chromatographic chiral stationary phase coupled to an achiral phenyl column

Wainer, Irving W.; Stiffin, Rose

doi:10.1016/s0378-4347(00)81088-9

Cited by 51 publications

(9 citation statements)

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“…This study was designed to evaluate the effect of the pharmacologically inactive d-diastereomer on the pharmacokinetics of the 1-diastereoisomer. Potential areas for interaction include: absorption, where saturation or dose dependency for 1-folates starts to show at doses above 25 mg of d,l-leucovorin [12,20]; metabolism, which is associated with the 1-folates but where potential inhibition by d-folates had not been investigated [12,13]; distribution, where active transport into cells and intracellular polyglutamation, a non-stereospecific reaction [24,25], could be affected by the presence of d-leucovorin; and elimination, where lack of the d-diastereoisomer could alter the moderate protein binding of the 1-folates and directly change renal clearance (filtration) of the active metabolite.…”

Section: Discussionmentioning

confidence: 99%

“…Data strongly suggest that virtually all of the pharmacologic activity resides with the naturally occurring 1-diastereomer [11]. The d-diastereomer is not metabolized [12,13] and therefore does not participate in the interconversion pathways required for reaction with dihydrofolate reductase; it binds only weakly to dihydrofolate reductase, it competes poorly with Meucovorin and methotrexate for cellular uptake, and has a lower binding affinity for intracellular polyglutamate formation [14][15][16].…”

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confidence: 99%

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Pharmacokinetic comparison of leucovorin and levoleucovorin

Zittoun

Tonelli²,

Marquet

et al. 1993

Eur J Clin Pharmacol

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The pharmacokinetic values of d,l-leucovorin and l-leucovorin were compared in eight healthy volunteers following oral administration of 25 mg d,l-leucovorin and 12.5 mg l-leucovorin. Serum levels of l-5-formyltetrahydrofolate, l-5-methyltetrahydrofolate, and total reduced folates were measured by an established microbiological method. Pharmacokinetic data for both preparations were consistent with those previously reported for d,l-leucovorin, with essentially complete first pass metabolism to l-5-methyltetrahydrofolate, the active metabolite. No differences were found between the two preparations in serum concentrations of active folate fractions, AUC, or Cmax, or in clearance and volume of distribution estimates. These data suggest that after administration of 25 mg of d,l-leucovorin, the d-diastereoisomer has no significant effect on the standard pharmacokinetic measurements of the active l-folates.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Pharmacokinetic comparison of leucovorin and levoleucovorin

Zittoun

Tonelli²,

Marquet

et al. 1993

Eur J Clin Pharmacol

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“…The respective test is performed by chiral HPLC employing a stationary phase of silica gel coated with human serum albumin. Chiral stationary phases containing human serum albumin [11] and bovine serum albumin [12][13][14][15][16] have also been used for the determination of levofolinic acid and 5-methyltetrahydrofolic acid in biological media but serum albumin stationary phases are hampered by a limited stability. In addition to the chiral assay, the European Pharmacopoeia limits related substances by an achiral reversed-phase HPLC method [10].…”

Section: Levofolinic Acid (2s)-2-[[4-[[[(6s)mentioning

confidence: 99%

Development and validation of a robust capillary electrophoresis method for impurity profiling of calcium levofolinate including the (6R,2'S)‐diastereomer using statistical experimental design

et al. 2004

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A chiral capillary electrophoresis assay for the simultaneous determination of the optical purity and of related substances of calcium levofolinate has been developed and validated. Using 2,6-dimethyl-beta-cyclodextrin as chiral selector at a concentration of 20 mg/mL, the method was optimized using a full factorial design with four factors including pH and concentration of the background electrolyte, column temperature and separation voltage. Optimized conditions were a 40 mM sodium tetraborate buffer, pH 9.9, a capillary temperature of 16 degrees C, and an applied voltage of 21 kV. Methotrexate was used as internal standard to compensate for injection errors and fluctuations of the migration times. A multiple linear regression model was also used to test the robustness of the method. Validation was performed with respect to specificity, linearity, range, limit of quantification and detection, precision, and accuracy. The assay allowed the detection and determination of related substances including the diastereomeric (6R,2'S)-impurity of levofolinic acid at the 0.1% level, the identification threshold of impurities for orally administered drugs for human use defined by the International Conference on Harmonization guidelines as well as the European Pharmacopoeia.

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“…However, only the S-enantiomer is active and rapidly taken up into cells. As a result, the vast majority of the measured plasma levels re¯ect the amount of the inactive R-enantiomer (Wainer and Stif®n, 1988;Shibukawa et al, 1993). This undermines the correlation between the plasma levels and the pharmacological effect.…”

Section: Clinical Issues Arising From Enantiomers' Differencesmentioning

confidence: 99%

The therapeutic promise of single enantiomers: introduction

Wainer

2001

Hum. Psychopharmacol. Clin. Exp.

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This review uses several examples drawn from the literature to show how using active enantiomers as therapeutic agents may yield several benefits, including more predictable pharmacokinetics, more accurate drug monitoring and enhanced tolerability. As a result of these benefits, the therapeutic use of single enantiomers will become increasingly important not only in psychopharmacology, but in medicine generally. Indeed, over the early years of the new millennium, the therapeutic use of single active enantiomers is set to redefine the benefit-risk ratio in the management of many common conditions. Copyright 2001 John Wiley & Sons, Ltd.

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Direct resolution of the stereoisomers of leucovorin and 5-methyltetrahydrofolate using a bovine serum albumin high-performance liquid chromatographic chiral stationary phase coupled to an achiral phenyl column

Cited by 51 publications

References 0 publications

Pharmacokinetic comparison of leucovorin and levoleucovorin

Pharmacokinetic comparison of leucovorin and levoleucovorin

Development and validation of a robust capillary electrophoresis method for impurity profiling of calcium levofolinate including the (6R,2'S)‐diastereomer using statistical experimental design

The therapeutic promise of single enantiomers: introduction

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