The (+)-enantiomer is responsible for the antiplatelet and anti-inflammatory activity of (±)-indobufen

Cerletti, Chiara; Manarini, Stefano; Colombo, Monica; Tavani, Alessandra

doi:10.1111/j.2042-7158.1990.tb07049.x

Cited by 22 publications

(10 citation statements)

References 8 publications

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“…Until now, INDB has been formulated as a racemic mixture even if its pharmacological activity is basically linked to its (+)-S-enantiomer. [3][4][5] Moreover, in healthy individuals no chiral inversion of the (+)-S-INDB form into the (−)-R form has been observed and higher levels of the latter form following administration of the racemic mixture are related to its slower elimination as compared to the (+)-S form. 5 Some nonsteroidal antiinflammatory drugs (NSAIDs), derivatives of 2-arylpropionic acid, e.g., ibuprofen, undergo chiral inversion, in which the pharmacologically inactive (−)-R form is transformed into its active (+)-S form.…”

Section: Resultsmentioning

confidence: 97%

Steady‐state pharmacokinetics of indobufen enantiomers in patients with obliterative atherosclerosis

2001

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Steady-state pharmacokinetics of indobufen (INDB) enantiomers administered as racemic INDB (rac-INDB) tablets and bleeding time were studied in patients. Two-hundred mg INDB tablets (Ibustrin) were administered twice daily for 7 days to obliterative atherosclerosis patients. Enantiospecific reversed phase (RP) HPLC with UV detection (lambda = 275 nm) was used for determination of INDB enantiomers in serum of patients. The ratio AUCR:AUCS equalled 1.7 +/- 0.2 as a result of higher (-)-R-enantiomer serum levels. The (+)-S-enantiomer was more rapidly eliminated (oral clearance, Cl = 1.1 +/- 0.3 L/h) than its (-)-R-antipode (Cl = 0.7 +/- 0.2 L/h). Therefore, the mean steady/state levels of (-)/R/enantiomer (13.5 +/- 3.8 mg/L) exceeded those of its (+)-S-enantiomer (7.8 +/- 1.8 mg/L). Furthermore, half-life (t1/2) was significantly shorter for (+)-S-INDB (t1/2 = 4.5 +/- 1.2 h as compared to (-)-R-INDB (t1/2 = 7.4 +/- 2.4 h). However, no significant differences were observed in the respective Vd values. The bleeding time of patients was not significantly extended. The above pharmacokinetic data provide a rationale for potential future replacement of INDB racemic tablets with tablets of its (+)-S-enantiomer.

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Section: Resultsmentioning

confidence: 97%

Steady‐state pharmacokinetics of indobufen enantiomers in patients with obliterative atherosclerosis

2001

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“…Although the cyclooxygenase-inhibiting activity resides principally in the (+)-S-enantiomer, [2][3][4] INDB has been used up to now in therapy as the racemate.…”

Section: -6mentioning

confidence: 99%

Protein binding of indobufen enantiomers: Pharmacokinetics of free fraction—studies after single or multiple doses of rac‐indobufen

Główka

Caldwell

2002

Chirality

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The binding of the enantiomers of indobufen (INDB) to human serum proteins was investigated using the racemic mixture or the pure (+)-S-enantiomer in a concentration range of 2.5-100.0 mg/L. In addition, the pharmacokinetics of free (unbound) and total INDB enantiomers were studied 1) following administration of a single 200 mg rac-INDB tablet to healthy volunteers, and 2) in obliterative atherosclerosis patients at steady state. The free fraction of INDB was obtained by ultrafiltration. Using the racemic mixture, the binding parameters of the two enantiomers were different, showing enantioselectivity in protein binding. The (-)-R-enantiomer was bound more strongly to human serum albumin, with association constant K = 11.95 +/- 0.98 x 10(5) M(-1) and n = 0.72 +/- 0.02 binding sites. The comparable data for the (+)-S-enantiomer were K = 4.65 +/- 0.02 x 10(5) M(-1), n = 0.92 +/- 0.01. When the binding of (+)-S-enantiomer was studied alone, the association constant K (2.10 +/- 0.18 x 10(5) M(-1)) was lower and the number of binding sites was increased, to n = 1.87 +/- 0.17. Competition occurred between the enantiomers, with the (-)-R-enantiomer displacing its antipode. The fraction of both enantiomers bound to serum proteins was 99.0%, which increased with decreasing initial concentration of the enantiomers. In healthy volunteers the (+)-S-enantiomer was eliminated faster than its (-)-R antipode, resulting in a lower AUC for the (+)-S-enantiomer. Significant differences were observed in the total INDB enantiomer concentrations. The mean unbound fraction of (-)-R- and (+)-S-INDB was 0.45% and 0.43%, respectively. Levels of the free (+)-S-enantiomer were higher than its (-)-R-antipode at steady state in patients with obliterative atherosclerosis who also took other drugs. The free enantiomer fraction increased to around 1% upon repeated administration. We conclude that the more rapid elimination of the (+)-S enantiomer is associated with its weaker binding to serum proteins.

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“…1) and exists in two enantiomeric forms as (−)-R and (+)-S. Its structure is similar to that of derivatives of 2-arylpropionic acid but profens ␣-methyl group is replaced by an ␣-ethyl group. Up to now, INDB has been used in the medical treatment as a racemate, though its anti-platelet and anti-inflammatory activity resides mainly in (+)-S-enantiomer (eutomer) [1][2][3][4]. After administration of rac-INDB to healthy volunteers [5,6] or patients with obliterative atherosclerosis [7], serum levels of the (+)-S enantiomer were significantly lower than those of the (−)-R antipode.…”

Section: Introductionmentioning

confidence: 99%

Resolution of indobufen enantiomers by capillary zone electrophoresis Pharmacokinetic studies of human serum

Główka

Karaźniewicz

2004

Journal of Chromatography A

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The (+)-enantiomer is responsible for the antiplatelet and anti-inflammatory activity of (±)-indobufen

Cited by 22 publications

References 8 publications

Steady‐state pharmacokinetics of indobufen enantiomers in patients with obliterative atherosclerosis

Steady‐state pharmacokinetics of indobufen enantiomers in patients with obliterative atherosclerosis

Protein binding of indobufen enantiomers: Pharmacokinetics of free fraction—studies after single or multiple doses of rac‐indobufen

Resolution of indobufen enantiomers by capillary zone electrophoresis Pharmacokinetic studies of human serum

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