Metabolism of Arylacetic Acids: 1. The Fate of 1-Naphthylacetic Acid and its Variation with Species and Dose

Abstract

1. [Carboxy-14C]-1-Naphthylacetic acid has been administered to man, 6 primate species and 4 other mammalian species and the urinary metabolites examined by radiochromatogram scanning and reverse isotope dilution. Animals all received a dose of 100 mg/kg and man received 5 mg, orally. 2. Most species excreted at least 60% of the 14C in the urine in 48 h. Unchanged acid was a minor (0-17% dose) excretion product in all species except the cynomolgus monkey (35%). 3. In man, in 24 h 95% of 14C was excreted as 1-naphthylacetyl-glucuronide and 5% as 1-naphthylacetyltaurine. 4. 1-Naphthylacetylglucuronide was the major excretion product in all species except the bushbaby (21% dose) and the cat, which did not form this conjugate. 5. 1-Naphthylacetylglutamine was formed only by the cynomolgus, squirrel and capuchin monkeys and marmoset, and in no case accounted for more than 3% dose. 6. 1-Naphthylacetylglycine was found in the urines of 4 primate and 3 non-primate species, and was the major metabolite in the squirrel monkey, bushbaby and cat. 7. 1-Naphthylacetyltaurine was excreted by all species except the rabbit and the fruit bat. It was a major excretion product in the squirrel and capuchin monkeys, the marmoset and the cat. 8. The influence of dose on the pattern of metabolism and excretion of 1-naphthylacetic acid has been investigated in the rat.

Species Differences in Metabolism and Pharmacokinetics of a Sphingosine-1-Phosphate Receptor Agonist in Rats and Dogs: Formation of a Unique Glutathione Adduct in the Rat

“…In addition, saturation of taurine conjugation with a corresponding increase in glucuronic acid conjugation of a peroxisome proliferator-activated receptor agonist was observed with increasing dose in dogs (Kim et al, 2004). A switch from amino acid (glycine) conjugation to glucuronic acid conjugation was also observed with increased doses after administration of 1-naphthylacetic acid to rats (Dixon et al, 1977). Furthermore, salicylate conjugation by glycine to salicyluric acid is saturated at therapeutic doses in humans (Levy, 1965a,b).…”

Species variation in the metabolism of 1-naphthylacetylglycylglycylglycine

“…l-Naphthylacetylglycine and l-naphthylacetylglucuronide were samples prepared by Dixon et al (6). l-Naphthylacetyl- (6) and was crystallized from ethanol, (m.pt. 239-241 "C; specific activity 0.114 J,.LCijmg).…”

“…The metabolites were identified by chromatography and reverse isotope dilution (6). Table II shows the metabolic profile of l-Naphthylacetylglycylglycylglycine in the species studied.…”

Drug metabolism in ”exotic” animals

“…This acid was of interest since in carnivores it appeared to be excreted partly as a conjugate with taurine, whilst in herbivores (rabbit, Indian fruit bat) and primates, taurine conjugation was either not found or occurred at a low level (18). Table 2 shows results with some "exotic" felines.…”

“…During this phase the compound usually acquires OH, COOH, NH2 or SH groups through which it can undergo the second phase, the reactions of which are syntheses, usually referred to as conjugations, which are also enzyme catalysed. This concept can be illustrated by the main metabolic reactions of benzene, for which the basic pattern is as follows (omitting details) : (16), phenylacetic acid (17) and o-naphthylacetic acid (18). Glucuronic acid conjugation, however, is not entirely absent from the domestic cat, since hydratropic and diphenylacetic acids are extensively conjugated with glucuronic acid in the cat (19,20) (see below).…”