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Biotransformation von ausgewählten Gyrasehemmern

Biotransformation of certain gyrase inhibitors

  • Pharmakokinetik
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Zusammenfassung

Die Gyrasehemmer Norfloxacin, Ciprofloxacin, Pefloxacin und Ofloxacin haben als gemeinsame Grundstruktur das 3-Carboxy-4-oxo-6-fluor-7-(1-piperazinyl)-1,4-dihydrochinolin. Sie durchlaufen verschiedene Biotransformationen, die an Tieren und teilweise auch beim Menschen beschrieben worden sind: 1. Konjugation der Carboxylgruppe mit Glukuronsäure. (Die Bildung des O-Methylesters von Norfloxacin ist nur bei der Ratte gefunden worden). 2. Oxidation des Piperazin-Ringes zur 3-Oxo-Verbindung und Abbau (oder Zerfall) des Piperazin-Ringes über mehrere Zwischenstufen bis zum vollständigen Abbau der Seitenkette. 3. Substitution des in Parastellung nicht besetzten Piperazin-Ringes zum N-Azetyl-bzw. N-Formyl-Derivat (Norfloxacin, Ciprofloxacin). 4. Demethylierung der 4-Methyl-piperazin-Seitenkette (Pefloxacin, Ofloxacin). 5. N-Oxidation der 4-Methyl-piperazin-Seitenkette (Pefloxacin, Ofloxacin). Die Glukuronide sind mikrobiologisch inaktiv. Die Aktivität der Produkte mit modifizierter Piperazin-Seitenkette wechselt von hoch (Oxo-Verbindungen) bis gering (nach Ringspaltung). Quantitative Daten über die Bildung der genannten Metabolite beim Menschen sind zur Zeit noch spärlich. Als Hauptmetabolit wird zumeist das Oxo-Derivat gefunden. Es ist anzunehmen, daß von einigen Substanzen in Zukunft noch weitere Metabolite identifiziert werden.

Summary

The common structure of the gyrase inhibitors norfloxacin, ciprofloxacin, pefloxacin, and ofloxacin is 3-carboxy-4-oxo-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-quinolone. Several biotransformations of these substances are reported in the literature, mostly in animals and partly in humans: 1. Conjugation of the carboxylic acid to glucuronic acid (formation of an O-methyl ester of norfloxacin was found only in the rat); 2. Oxidation of the piperazine ring to the oxo derivative and subsequent metabolisation (or degradation) of the piperazine ring to several intermediates and finally to elimination of the side chain; 3. Substitution of the piperazine side chain to the 4-N-acetyl or 4-N-formylderivative (norfloxacin, ciprofloxacin); 4. Methylation of the 4-methyl-piperazine side chain (pefloxacin, ofloxacin). 5. N-oxidation of the 4-methyl-piperazine side chain (pefloxacin, ofloxacin). The glucuronides are microbiologically inactive. The activity of metabolites with a modified piperazine side chain varies from high (oxo derivatives) to low (after splitting of the ring). Quantitative data on the formation of the described transformation products in humans are presently still incomplete. The oxo derivative appears to be the main metabolite of norfloxacin and ciprofloxacin. Aditional metabolites to the described ones are likely to be detected in the near future.

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Authors and Affiliations

  1. Institut für Klinische Chemie und Klinische Biochemie, Klinikum Steglitz der Freien Universität, Hindenburgdamm 30, D-1000, Berlin 45

    K. Borner

  2. Medizinische Klinik und Poliklinik, Klinikum Steglitz der Freien Universität, Hindenburgdamm 30, D-1000, Berlin 45

    H. Lode

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  1. K. Borner
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  2. H. Lode
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Borner, K., Lode, H. Biotransformation von ausgewählten Gyrasehemmern. Infection 14 (Suppl 1), S54–S59 (1986). https://doi.org/10.1007/BF01645200

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