Abstract
Because of previously observed species differences in rhein tolerability, with rabbits being very susceptible to kidney disturbances, in vivo and in vitrobiotransformation studies were performed to find out whether the differences in the undesired effects of rhein are associated with qualitative, species-dependent differences in its metabolism. First hints on species-dependent biotransformation profiles were obtained from in vivo experiments with14C-labeled rhein in rat, rabbit, dog, and man. TLC-analysis of urine samples obtained after oral administration of14C-rhein to rabbits revealed an additional, hydrophilic metabolite fraction in rabbit urine as compared with dog and human urine, all of which contain phenolic monoglucuronide and monosulfate as major metabolites. An investigation of urine samples (obtained from dogs, rabbits, rats, and human volunteers after oral application of unlabeled rhein) was conducted by means of mass spectrometric tandem techniques including on-line HPLC-MS/MS. In vitro experiments with subcellular liver fractions of rats and rabbits revealed the presence of three monohydroxylated metabolites of rhein, their quinoid oxidation products, and a bishydroxylated derivative of rhein. The hydroxylated phase I metabolites were detected as glucuronides in urine samples of all investigated species, whereas the quinoid product was present only in rabbit urine. Moreover, two regioisomeric phenolic glucuronides and sulfates or glucosides of rhein were found as major phase II metabolites in urine of all species. Furthermore, acyl glucuronides of rhein and monohydroxylated rhein and their respective isomeric acyl migration products were identified in human urine. In rabbit urine we discovered different bisglucuronides (bisphenolic glucuronide, mixed ether/ester glucuronides), whereas in rats only the bisether/ether glucuronide was present. In addition, the investigations of dog and human urine showed the formation of two regioisomeric phenolic glucosides.
With respect to a potential reactivity with endogenous macromolecules the quinoid metabolites as well as the bisester/ether glucuronides appear most relevant.
Footnotes
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Send reprint requests to: Monika Dahms, Department of Pharmacology, für Naturwissenschaftler, Biozentrum Niederursel, Johann-Wolfgang Goethe-Universität, Marie-Curie-Str. 9, Geb. ND-60439 Frankfurt, Germany.
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2 M. Dahms, E. Mutschler, W. Lang, R. Lotz, U. Renner, R. Weyhenmeyer, K. P. Zeller, and H. Spahn-Langguth: Untersuchungen zum Phase I und Phase II Metabolismus von Rhein bei verschiedenen Spezies. Wissenschaftliches Programm mit Kurzreferaten, Annual Meeting of Deutsche Pharmazeutische Gesellschaft,Jena, 1995, p. 108.
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3 M. Dahms, R. Lotz, E. Mutschler, W. Lang, R. Weyhenmeyer, and H. Spahn-Langguth: Species differences in rhein biotransformation: formation of potentially reactive metabolites. Naunyn-Schmiedeberg’s Arch. Pharmacol.353(Suppl.), No. 4, R149 (1996).
- Abbreviations used are::
- Rhein
- 1,8-dihydroxy-anthraquinone-3-carboxylic acid
- 14C-labeled rhein
- 1,8-dihydroxy [9-14C] anthraquinone-3-carboxylic acid
- TEA
- triethylamine
- amu
- atomic mass unit
- Received August 26, 1996.
- Accepted January 1, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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