PT  - JOURNAL ARTICLE
AU  - Dahms, Monika
AU  - Lotz, Ralf
AU  - Lang, Werner
AU  - Renner, Ulf
AU  - Bayer, Ernst
AU  - Spahn-Langguth, Hildegard
TI  - Elucidation of Phase I and Phase II Metabolic Pathways of Rhein: Species Differences and Their Potential Relevance
DP  - 1997 Apr 01
TA  - Drug Metabolism and Disposition
PG  - 442--452
VI  - 25
IP  - 4
4099  - http://dmd.aspetjournals.org/content/25/4/442.short
4100  - http://dmd.aspetjournals.org/content/25/4/442.full
SO  - Drug Metab Dispos1997 Apr 01; 25
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics