Stereoselective protein binding of verapamil enantiomers

Gross, Annette S.; Heuer, B.; Eichelbaum, Michel

doi:10.1016/0006-2952(88)90330-9

Cited by 68 publications

(26 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Methodological differences seem an unlikely explanation for the discrepancy between the two studies because predose protein binding was essentially identical. In the current study, however, subjects received a commercially available 240 mg sustained release dose of rac-verapamil, while in the study by Gross et al [2], subjects were given 80 mg d2-(+)-verapamil and 80 mg unlabelled (-)-verapamil simultaneously. In their intravenous administration studies, labelled and unlabelled verapamil enantiomers were administered separately.…”

Section: Resultsmentioning

confidence: 84%

“…Table 1 Average free fractions (mean ± s.d.) of R-and Sverapamil in eight human subjects before, following a single dose, and after multiple doses of 240 mg sustained release racemic oral verapamil Enantiomer Predose Single dose Steady state R-verapamil 0.051 ± 0.012 0.050 ± 0.008 0.051 ± 0.008 S-verapamil 0.097 ± 0.023 0.093 ± 0.017 0.094 ± 0.010 Table 2 Influence of norverapamil, D617, and D620 on the fraction unbound (mean ± s. [2] hypothesized that the two-fold increase in the free fraction of R-and S-verapamil following oral verapamil administration was due to metabolite accumulation. The results of the current study do not support either their findings or their hypothesis.…”

Section: Resultsmentioning

confidence: 99%

“…A recent study by Gross et al [2] showed that Rand S-verapamil unbound fractions were two-fold higher in plasma samples collected from the subjects taking oral verapamil, than in the same subjects prior to dosing or following an intravenous dose. As a result of extensive first-pass metabolism, verapamil metabolite concentrations are higher following oral dosing than following intravenous dosing [1].…”

Section: Introductionmentioning

confidence: 97%

“…Currently available verapamil products are administered as a racemic mixture of its R-and S-enantiomers and it is well recognized that the enantiomers of verapamil differ in both their pharmacokinetic properties and pharmacological activity [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Influence of metabolites on protein binding of verapamil enantiomers.

Johnson

Akers

1995

Brit J Clinical Pharma

View full text Add to dashboard Cite

This study investigated the effect of verapamil metabolites on R‐ and S‐ verapamil protein binding in plasma samples collected from subjects prior to rac‐verapamil dosing and following single dose and steady state rac‐verapamil dosing. In vitro studies of the effects of norverapamil, D617 and D620 on R‐ and S‐verapamil protein binding were also performed. Protein binding of R‐ and S‐verapamil was unchanged following single and multiple doses of rac‐verapamil as compared with protein binding in pre‐dose samples. In vitro, norverapamil had no effect on R‐ and S‐verapamil protein binding up to 1000 ng ml‐1. Norverapamil 5000 ng ml‐1 caused a 30% increase in free fraction of both R‐ and S‐verapamil. D617 and D620 concentrations up to 5000 ng ml‐ 1 had no effect on R‐ and S‐verapamil protein binding. We conclude the metabolites of verapamil have no clinically significant effect on R‐ and S‐verapamil protein binding.

show abstract

Section: Resultsmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Influence of metabolites on protein binding of verapamil enantiomers.

Johnson

Akers

1995

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…This selectivity is in consistent with the previous result that (R)-VER is bound more strongly than (S)-VER in human plasma. 30 The detection limit was 5 nM (S/N=3) for each enan- amount.…”

Section: Resultsmentioning

confidence: 95%

On-Capillary Sample Preconcentration Incorporated in Chiral Capillary Electrophoresis

Shibukawa

Zeng

et al. 1996

ANAL. SCI.

View full text Add to dashboard Cite

The on-capillary sample enrichment technique was developed to improve the sensitivity of UV-detection in capillary electrophoresis (CE). The enrichment was achieved in a preconcentration zone (zone length 2 mm) filled with the packing material used for HPLC, which is fixed by an inner frit near to the inlet of the capillary. The feasibility of this technique was demonstrated by chiral separation of a low concentration of verapamil (VER, a calcium channel blocker) enantiomers. The preconcentration procedure involves initial conditioning of the capillary, hydrodynamic sample introduction, washing of adsorbed VER, and its transfer to the capillary. Enriched VER was separated into enantiomers using a chiral selector (25 mM trimethyl-a-CD) dissolved in the run buffer (pH 2.5). The detection limit was 5 nM, about 200-times lower than that without preconcentration.The detection response indicated good linearity against the concentration of VER over the 10 -100 nM range for each enantiomer (r>0.999). The present CE system was applied to determine the unbound concentration of VER enantiomers in human plasma after ultrafiltration.

show abstract

Pharmacokinetics of the Enantiomers of Verapamil After Intravenous and Oral Administration of Racemic Verapamil in a Rat Model

Bhatti

Foster

1997

Biopharm. Drug Dispos.

View full text Add to dashboard Cite

Verapamil is a chiral calcium channel blocking drug which is useful clinically as the racemate in treating hypertension and arrhythmia. The published pharmacokinetic data for verapamil enantiomers in the rat model are limited. Utilizing a stereospecific high‐performance liquid chromatographic (HPLC) assay, the enantiomeric disposition of verapamil is reported after intravenous (1·0 mg kg−1) and oral (10 mg kg−1) administration of racemic verapamil to the rat model. After intravenous administration the systemic clearance of R‐verapamil was significantly greater than that of S‐verapamil; 34·9 ± 7 against 2·7 ± 3·7 mL min−1 kg−1 (mean ± SD), respectively. After oral administration, the clearance of R‐verapamil was significantly greater than that of S‐verapamil, 889 ± 294 against 351 ± 109 mL min−1 kg−1, respectively. The apparent oral bioavailability of S‐verapamil was greater than that of R‐verapamil, 0·074 ± 0·031 against 0·041 ± 0·011, respectively. These data suggest that the disposition of verapamil in the rat is stereoselective; verapamil undergoes extensive stereoselective first‐pass clearance after oral administration and the direction of stereoselectivity in plasma is opposite to that observed in the human. © 1997 John Wiley & Sons, Ltd.

show abstract

Stereoselective protein binding of verapamil enantiomers

Cited by 68 publications

References 20 publications

Influence of metabolites on protein binding of verapamil enantiomers.

Influence of metabolites on protein binding of verapamil enantiomers.

On-Capillary Sample Preconcentration Incorporated in Chiral Capillary Electrophoresis

Pharmacokinetics of the Enantiomers of Verapamil After Intravenous and Oral Administration of Racemic Verapamil in a Rat Model

Contact Info

Product

Resources

About