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Pharmacokinetics, cardiovascular and metabolic actions of cyclohexylamine in man

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Abstract

Cyclohexylamine (CHA) a possible metabolite of the artificial sweetener cyclamate was administered orally in doses of 2.5, 5 and 10 mg/kg b.w. to healthy volunteers. Plasma half lives of CHA ranged from 3.5 to 4.8 h showing a clear dose dependency. 86 to 95 % of the dose administered was excreted in the urine during 48 h as unchanged drug. Since CHA is a fairly strong base with a pKa of 10.6 the almost complete enteral absorption was rather unexpected. Cyclohexylamine caused a dose dependent rise in arterial blood pressure. A close correlation between plasma levels of CHA and increase of mean arterial blood pressure could be established. The analysis of this concentration response curve revealed that plasma levels of CHA of about 0.7 to 0.8 μg/ml are required in order to cause a significant increase in arterial blood pressure. A significant increase in plasma free fatty acids and cumulative urinary excretion of catecholamines was observed only after the administration of 10 mg/kg b.w. CHA. Our findings are consistent with cyclohexylamine being an indirect acting sympathomimetic amine which is some orders of magnitude less potent than related sympathomimetic substances.

Zusammenfassung

Cyclohexylamin — ein Stoffwechselprodukt des künstlichen Süßstoffes Cyclamat — wurde in Dosen von 2,5, 5 und 10 mg/kg KG oral an gesunde Versuchspersonen verabreicht. Die Plasmahalbwertszeit von CHA betrug 3,5 bis 4,8 Std, wobei eine deutliche Abhängigkeit der Halbwertszeit von der applizierten Dosis beobachtet werden konnte. 86 bis 95% der verabfolgten Dosis wurden innerhalb 48 Std als unverändertes CHA im Urin ausgeschieden. Da Cyclohexylamin mit einem pKa von 10.6 eine stark basische Substanz ist, ist die fast vollständige enterale Resorption, ermittelt über die cumulative Urinausscheidung, als unerwartet hoch anzusehen. CHA verursachte einen dosisabhängigen Blutdruckanstieg, wobei eine enge Beziehung zwischen Blutdruckanstieg und den Cyclohexylaminplasmaspiegeln aufgestellt werden konnte. Auf Grund dieser Blutspiegel-Wirkungskurve konnte gezeigt werden, daß für einen signifikanten Blutdruckanstieg der kritische Cyclohexylaminplasmaspiegel zwischen 0,7 bis 0,8 μg/ml liegt. 10 mg/kg K.G. Cyclohexylamin verursachten einen signifikanten Anstieg der unveresterten Plasma-Fettsäuren und der cumulativen Katecholaminausscheidung im Harn, wohingegen Dosen von 2,5 und 5 mg/kg ohne Effekt waren.

Diese Ergebnisse zeigen, daß CHA ein indirektes Sympathikomimetikum ist, das allerdings wesentlich weniger wirksam ist als verwandte sympathikomimetische Substanzen.

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Authors and Affiliations

  1. Department of Medicine, Justus Liebig University, Giessen, Germany

    M. Eichelbaum, J. H. Hengstmann, H. D. Rost, T. Brecht & H. J. Dengler

  2. Medizinische Universitätsklinik, D-5300, Bonn Venusberg, Federal Republic of Germany

    M. Eichelbaum

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  1. M. Eichelbaum
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  2. J. H. Hengstmann
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  3. H. D. Rost
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  4. T. Brecht
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  5. H. J. Dengler
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Additional information

This investigation was supported by the “Deutsche Forschungsgemeinschaft” (grant De 44/5).

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Eichelbaum, M., Hengstmann, J.H., Rost, H.D. et al. Pharmacokinetics, cardiovascular and metabolic actions of cyclohexylamine in man. Arch. Toxicol. 31, 243–263 (1974). https://doi.org/10.1007/BF00311057

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