The Significance of Metabolic Sites, Especially Lack of Ring Hydroxylation
Abstract
The metabolism of probenecid was studied in animals (dogs, monkeys, and rats). The metabolites of probenecid, with one exception, were shown to be terminal metabolites in dogs and rats in vivo and in rats in vitro. One of the alcohol metabolites is further oxidized to the carboxy metabolite. Evidence was obtained that in rats neither ring oxidation of probenecid nor its incorporation into the macromolecular fraction of liver microsomes occurred. The lack of ring oxidation was attributed to the deactivating influence of the ring substituents. These electronic effects (and possibly steric effects) presumably channel metabolism either to the side chain (microsomal oxidation) or to the carboxyl group (conjugation with glucuronic acid). Species differences were observed among the animals studied in the metabolism of probenecid and its piperidyl analog. Probenecid exhibited an unusually short plasma half-life in the monkey. The results with probenecid and its analog suggest that molecular modification of drugs could be oriented in such a way as to prevent ring oxidation, but without loss of pharmacologic activity. The advantage of such a course lies in avoiding formation of epoxide intermediates, which in the case of some drugs, due to their reactivity, might result in toxicity.
Footnotes
- Received June 21, 1973.
- Copyright © 1973 by The American Society for Pharmacology and Experimental Therapeutics