On chiral drug action

Simonyi, Miklós

doi:10.1002/med.2610040304

Cited by 125 publications

(45 citation statements)

References 362 publications

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“…these interactions occur in an asymmetric fashion. Keeping this in mind, it seems obvious that artificial drugs have to be chiral to be integrated correctly in the vast and complex game of molecular interactions of living systems [5]. In fact, it has been demonstrated that in many cases, while they behave similarly in a symmetric environment, two enantiomers of the same molecule have different effects in biological systems [6].…”

Section: Introductionmentioning

confidence: 99%

A Cyclodextrin Self-Assembled Monolayer (SAM) Based Surface Plasmon Resonance (SPR) Sensor for Enantioselective Analysis of Thyroxine

Shahgaldian

Hegner

Pieles³

2005

J Incl Phenom Macrocycl Chem

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Heptakis{6-deoxy-6-[12-(thiododecyl) undecanamido-b-cyclodextrin has been produced by reaction of Heptakis(6-deoxy-6-amino)-b-cyclodextrin and 12-(thiododecyl)undecanoic acid using O-Benzotriazol-1-yl-N,N,N¢,N¢-tetramethyluronium tetrafluoroborate (TBTU) as activating agent. Self-assembled monolayers of this macrocycle have been used in a surface plasmon resonance (SPR) sensor; it has been shown that this system is suitable to discriminate between D and L enantiomers of thyroxine, with a greater affinity for the D -enantiomer.

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Section: Introductionmentioning

confidence: 99%

A Cyclodextrin Self-Assembled Monolayer (SAM) Based Surface Plasmon Resonance (SPR) Sensor for Enantioselective Analysis of Thyroxine

Shahgaldian

Hegner

Pieles³

2005

J Incl Phenom Macrocycl Chem

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“…The percentage of the dose recovered as metabolites was significantly lower for R-nitrendipine. Comparison of cumulative urinary excretion of metabolites for the (Roth & Kleemann, 1982;Simonyi, 1984). In spite of the widespread therapeutic use of racemates data on the activity and disposition of the enantiomers are sparse.…”

Section: Protein Bindingmentioning

confidence: 99%

Use of pseudoracemic nitrendipine to elucidate the metabolic steps responsible for stereoselective disposition of nitrendipine enantiomers.

Mast

Fischer

Mikus

et al. 1992

Brit J Clinical Pharma

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1 The pharmacokinetics, protein binding, bioavailability and metabolism of (+)-R-and (-)-S-nitrendipine were studied in six healthy subjects following random oral administration of 20 mg (+)-R-, 20 mg (-)-S-and 20 mg R,S-nitrendipine (pseudoracemic mixture of 10 mg [13C4)-(+)-R-and 10 mg (-)-S-enantiomer). 2 After administration of the enantiomers pronounced differences in AUC (R: 29.9 + 20.1; S: 123.8 ± 63.7 ng ml-' h; P < 0.05), bioavailability (R: 10.7 ± 7.4%; S: 44.6 + 23.1%; P < 0.05) and Cmax (R: 14.4 ± 7.7; S: 72.5 ± 40.5 ng ml-1; P < 0.05) were observed between R-and S-nitrendipine. When racemic nitrendipine was given bioavailability and dose normalized AUC and Cmax values of the S-enantiomer were not different from the values after S-nitrendipine-administration. In constrast, bioavailability (R: 10.7% R,S: 22.1%) and dose normalized AUC (R: 15.0; R,S: 29.5 ng ml-1 h and Cmax (R: 7.2; R,S: 16.8 ng ml-') of R-nitrendipine were doubled following R,S-as compared with R-nitrendipine administration. t½/2 (R: 9.8; S: 9.1 h) and tmax were not different between the enantiomers nor were the values different after administration of the enantiomers or racemate. The fraction unbound in serum of R-nitrendipine was 0.0098 ± 0.0032 (s.d.) and that of S-nitrendipine was 0.0083 + 0.0015 (s.d.). 3 The AUC values of the major pyridine metabolite Ml were similar after administration of R-and S-nitrendipine (S: 114.7 ± 48.5; R: 71.7 ± 29.9 ng ml-' h). After racemic nitrendipine dose normalized AUC values were not different from those observed after administration of the enantiomers. 4 The cumulative urinary excretion of the four major pyridine metabolites M2a, M2b, M3a and M3b was significantly higher after S-nitrendipine. The % of dose which was recovered in urine within 48 h was 63.2 ± 6.6% (administration of racemate)/69.0 ± 5.9% (administration of S-enantiomer) for the S-enantiomer and 42.0 ± 5.1% (R,Snitrendipine)/43.8 ± 7.6% (R-enantiomer) for the R-enantiomer, respectively. Formation of metabolite M2a, which is generated by cleavage of the ethyl ester bond and oxidation of the 1,4-dihydropyridine ring to pyridine, exhibited stereoselectivity. On average 43.9 ± 3.9% of dose was formed from S-nitrendipine as compared with 24.7 ± 2.2% from R-nitrendipine following administration of the racemate. 5 Substantial differences in the metabolism, bioavailability and disposition of R-and Snitrendipine were observed. The first-pass metabolism of nitrendipine is stereoselective affecting mainly the less potent R-enantiomer. The bioavailability of R-nitrendipine doubled after administration of the racemate as compared with R-nitrendipine suggesting a metabolic enantiomer-enantiomer interaction with the S-enantiomer acting as an inhibitor of R-nitrendipine metabolism. With regard to the metabolic pathways responsible for stereoselective first-pass metabolism, it is unlikely that oxidation of nitrendipine to the pyridine metabolite Ml is involved since no substantial differences in the AUC of this metabolite were observed after admi...

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“…Current awareness of the different actions that may be exerted by the two enantiomers of a chiral substance provided with biological activity has prompted an increasing interest in methods to characterize their stereochemistry, i.e., to determine the enantiomeric composition and the absolute configuration of the single enantiomers. [1][2][3][4][5][6][7][8][9][10][11][12] As far as the enantiomeric composition is concerned, separation methodologies represent the most reliable choice. In particular, HPLC on chiral stationary phases had a tremendous impact in the field, and its application incredibly increased, as well as the use of capillary electrophoresis.…”

mentioning

confidence: 99%

“…In particular, HPLC on chiral stationary phases had a tremendous impact in the field, and its application incredibly increased, as well as the use of capillary electrophoresis. [1][2][3][4] A complete stereochemical characterization of a chiral drug can be reliably obtained by coupling the HPLC technique on chiral stationary phases with a detection system based on the measurement of the chiroptical properties (optical rotation or circular dichroism, CD). [5][6][7][8][9][10][11][12] When the separation has been obtained the use of CD, or a polarimeter, as a detection system allows determination of the stereochemistry of each eluate working at a single wavelength.…”

mentioning

confidence: 99%

Reliable assay of extreme enantiomeric purity values by a new circular dichroism based HPLC detection system

et al. 2000

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On chiral drug action

Cited by 125 publications

References 362 publications

A Cyclodextrin Self-Assembled Monolayer (SAM) Based Surface Plasmon Resonance (SPR) Sensor for Enantioselective Analysis of Thyroxine

A Cyclodextrin Self-Assembled Monolayer (SAM) Based Surface Plasmon Resonance (SPR) Sensor for Enantioselective Analysis of Thyroxine

Use of pseudoracemic nitrendipine to elucidate the metabolic steps responsible for stereoselective disposition of nitrendipine enantiomers.

Reliable assay of extreme enantiomeric purity values by a new circular dichroism based HPLC detection system

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