Drug biotransformation interactions in man II: A pharmacokinetic study of the simultaneous conjugation of Benzoic and Salicylic Acids with Glycine
✍ Scribed by Lewis P. Amsel; Gerhard Levy
- Publisher
- John Wiley and Sons
- Year
- 1969
- Tongue
- English
- Weight
- 587 KB
- Volume
- 58
- Category
- Article
- ISSN
- 0022-3549
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✦ Synopsis
The major route of biotransformation of benzoic acid and salicylic acid in man is conjugation with glycine, resulting in the formation of hippuric acid and salicyluric acid, respectively. Both processes are capacity-limited in the usual dose range and approach a maximum rate following administration of sufficiently high doses of precursor. The rate of hippuric acid formation after oral administration of 5 g. benzoic acid in solution is increased markedly by the concomitant administration of glycine. In contrast, the administration of glycine has no effect on the formation of salicyluric acid. Salicylic acid in doses of 1 to 3 g. given orally 2 or 3 hr. prior to 2.0 to 5.0 g. benzoic acid had no measurable effect on the formation of hippuric acid. However, benzoic acid has a pronounced inhibitory effect on the formation of salicyluric acid from salicylic acid. This effect was not prevented by the co-administration of glycine. These results indicate that in man the availability of glycine is rate-limiting in the formation of hippuric acid, but not in the formation of salicyluric acid. Apparently, the inhibitory effect of benzoic acid on the formation of salicyluric acid is not due to competition for glycine but involves another phase in the biotransformation process.
Keyphrases 0 Biotransformation interactionsarugs 0 Pharmacokinetics-benzoic, salicylic acids, simultaneous glycine conjugation 0 Salicylic acid effect-hippurate, benzoyl glucuronide formation, benzoic acid 0 Benzoic acid effect-salicyluric acid formation, salicylic acid 0 Glycine effect-benzoic, salicylic acid elimination 0 UV spectrophotometry-analysis
The elimination of salicylate in man is due mainly to its conjugation with glycine, i.e., the formation of salicyluric acid (1). Since man has a limited capacity for salicylurate formation, the time necessary to eliminate a given fraction of a dose of salicylate increases with increasing dose except in the very low dose range (1, 2). These pharmacokinetic characteristics of salicylate cause this drug to be readily accumulated in the body so that chronic administration may result in intoxication, particularly in young children (3). Treatment of salicylate intoxication is based largely on measures which accelerate the elimination of this drug from the body. It is evident, therefore, that a better understanding of the mechanism and pharmacokinetics of salicylurate formation may lead to safer salicylate therapy and to more effective treatment of salicylate intoxications.
The elimination of benzoic acid in man is due almost exclusively to the conjugation of this drug with glycine, resulting in the formation of hippuric acid (4). This involves the following mechanism: benzoic acid + ATPI+ adenylbenzoate + pyrophosphate adenylbenzoate + CoA* + benzoyl-CoA + adenylic acid benzoyl-CoA + glycine + hippuric acid + CoA