Disposition of a series of tetrahydrocarbazoles.
Cyclindole was extensively metabolized and eliminated primarily via the kidneys from most laboratory animals and man. Only in the dog was cyclindole a major urinary component. Cyclindole was metabolized by N-demethylation and/or hydroxylation. In studies utilizing radiolabeled drug, the primary urinary component was polar material which probably resulted from conjugation of the hydroxylated products. When desmethylcyclindole was administered to rats and dogs, large amounts of unchanged drug were administered to rats and dogs, large amounts of unchanged drug were recovered in the urine; there was no 3-aminotetrahydrocarbazole present. Significant amounts of urinary radioactivity were thought to represent hydroxylated and/or conjugated products. When 7-hydroxycyclindole was administered to dogs, only free parent drug was recovered from the urine; there was no evidence for N-demethylation. Flucindole, the 6,8-difluoro analog of cyclindole was metabolized by dog and man via N-demethylation with the formyl derivative being a probable intermediate in this reaction; both products were found in the urine. No didesmethyl metabolite was detected. In contrast to cyclindole, the N-oxide of flucindole was found in urine from both species. The route of elimination of oxarbazole and its metabolites was species specific: urinary excretion was 96.5, 38.7, 24.5, and 2.0% for the guinea pig, monkey, rat, and dog, respectively. The major urinary metabolite was O-demethyl oxarbazole; this metabolite was conjugated in all species except the guinea pig. The dog and monkey excreted small quantities of conjugated N-debenzoylated oxarbazole in urine. The profound changes in pharmacological activity that result from relatively small chemical modifications of the tetrahydrocarbazole nucleus make it likely that many further investigations of this class of compounds will be undertaken in the future.
D000818:Animals; D001711:Biotransformation; D002227:Carbazoles / Q000378:metabolism*; D007700:Kinetics
D002227:Carbazoles; C018095:3-methylamino-1,2,3,4-tetrahydrocarbazole; C029513:7-hydroxycyclindole; C029514:flucindole; C016025:oxarbazole; C014432:cyclindole