Pharmacokinetics of naproxen, its metabolite O-desmethylnaproxen, and their acyl glucuronides in humans.

The aim of this investigation was to assess the pharmacokinetics of naproxen in 10 human subjects after an oral dose of 500 mg using a direct HPLC analysis of the acyl glucuronide conjugates of naproxen and its metabolite O-desmethylnaproxen. The mean t1/2 of naproxen in 9 subjects was 24.7 +/- 6.4 h (range 16 to 36 h). The t1/2 of 7.4 as found in subject number 10 must, therefore, be regarded as an extraordinary case (p < 0.0153). Naproxen acyl glucuronide accounts for 50.8 +/- 7.32 per cent of the dose, its isomerized conjugate isoglucuronide for 6.5 +/- 2.0 per cent, O-desmethylnaproxen acyl glucuronide for 14.3 +/- 3.4 per cent, and its isoglucuronide for 5.5 +/- 1.3 per cent (n = 10; 100 h collection period). Naproxen and O-desmethylnaproxen are excreted in negligible amounts (< 1 per cent). Even though urine pH of the subjects was kept acid (range pH 5.0-5.5) in order to stabilize the acyl glucuronides, isomerization takes place in blood when the acyl glucuronide is released from the liver for excretion by the kidney. Binding to plasma proteins was measured as 98 per cent and 100 per cent, respectively for the unconjugated compounds naproxen and O-desmethylnaproxen. Binding of the acyl glucuronides was less, being 92 per cent; for naproxen acyl glucuronide, 66 per cent for naproxen isoglucuronide, 72 per cent for O-desmethylnaproxen acyl glucuronide and 42 per cent for O-desmethylnaproxen isoglucuronide.

Novel oxidative pathways of sulphapyridine and sulphadiazine by the turtle Pseudemys scripta elegans.

The sulphonamides sulphapyridine and sulphadiazine show novel hydroxy metabolites in the turtle Pseudemys scripta elegans. In the excreta of the turtles the monohydroxy metabolites 4-hydroxy- and 5-hydroxysulphapyridine and the dihydroxy metabolite 4,5-dihydroxysulphapyridine were detected. Of sulphadiazine only dihydroxy metabolites 4,5- and 4,6-dihydroxysulphadiazine were detected. About 70-90% of the dose of sulphapyridine was recovered, while this figure varied between 48 and 69% for sulphadiazine.

O-dealkylation and acetylation of sulphamethomidine by the turtle Pseudemys scripta elegans.

The turtle Pseudemys scripta elegans acetylates and O-dealkylates sulphamethomidine. The yield of acetylation (3.1%) is about 0.7 times greater than the yield of O-dealkylation (4.3%).

O-demethylation and N4-acetylation of sulphadimethoxine by the turtle Pseudemys scripta elegans.

After an oral dose of 350 mg of sulphadimethoxine, the turtle Pseudemys scripta elegans O-dealkylates sulphadimethoxine at the 2- and 6-position at 38% and 19% respectively, the 2-position being favoured. Acetylation of sulphadimethoxine and its hydroxy metabolites occurs for 57.4%.

Oxidation and O-dealkylation of sulphamonomethoxine by the turtle Pseudemys scripta elegans.

Sulphamonomethoxine is O-demethylated at the 6 position and oxidised at the 2 position of the pyrimidine substituent by Pseudemys scripta elegans. No N4-acetylation takes place. The yield of the oxidation reaction is twice that of the O-demethylation reaction.

N-oxidation, O-demethylation, and excretion of trimethoprim by the turtle Pseudemys scripta elegans.

Trimethoprim was excreted within one hour after being given orally to the turtle Pseudemys scripta elegans. No O-demethylated or N-oxide metabolites were detected.

Excretion and metabolism of a series of xanthines by the turtle Pseudemys scripta elegans.

The xanthines paraxanthine, xanthine, and uric acid are absorbed completely by the turtle Pseudemys scripta elegans and metabolised presumably into CO2 and NH3. No intermediate metabolites are excreted. Caffeine, hydroxycaffein, theobromine, hydroxytheobromine, and hydroxypraxanthine are absorbed and excreted in different amounts or percentages of the dose administered. Intermediate metabolites of these compounds are not excreted. The turtle Pseudemys scripta elegans may, therefore, be ammonotelic.

N-oxidation, N-demethylation, and excretion of pefloxacin by the turtle Pseudemys scripta elegans.

Pefloxacin is minimally absorbed by the gastrointestinal tract of the turtle Pseudemys scripta elegans and then N-oxidised and N-demethylated. Pefloxacin is excreted within one hour after being given orally to the turtles.

Hydroxylation and oxidation of nalidixic acid in the turtle Pseudemys scripta elegans.

The turtle Pseudemys scripta elegans hydroxylates nalidixic acid into 7-hydroxynalidixic acid; this latter metabolite is oxidised into 7-carboxynalidixic acid. The elimination half-life of nalidixic acid in the turtle is 30 h. No glucuronides of nalidixic- and 7-hydroxynalidixic acid are formed, as they are in man.

Acetylation, deacetylation and hydroxylation of sulphamethoxazole and N4-acetylsulphamethoxazole in the turtle Pseudemys scripta elegans.

The turtle Pseudemys scripta elegans is able to hydroxylate and acetylate Sulphamethoxazole in a way that is comparable to man, i.e. the rate and yield of hydroxylation equals that of the acetylation. The hydroxy metabolites 5-hydroxy- and N4-acetyl-5-hydroxysulphamethoxazole are not glucuronidated. N4-acetylsulphamethoxazole is neither deacetylated nor hydroxylated.

Excretion rates of sulfamethoxazole and N4-acetyl-sulfamethoxazole by fresh water turtles Pseudemys scripta elegans.

Sulfamethoxazole and N4-acetylsulfamethoxazole are excreted by fresh water turtles Pseudemys scripta elegans in a biphasic mode, characterized half-lives of 5 and 100 min. Acetylation and deacetylation reactions cannot be detected below a dose of 50 mg/kg. The mass balance of the dose administered is incomplete, only 30 per cent of the dose can be recovered as parent compound and metabolite. The sulfonamides must be mainly excreted by the faeces and may be metabolized in the gastro-intestinal tract.