Metabolism of pentaerythritol trinitrate.

The absorption, excretion, and biotransformation of 14C-labeled pentaerythritol (PE) trinitrate was studied in man. The administration of a single sublingual dose was followed by rapid absorption and extensive biotransformation. Six drug metabolites were identified. Final excretion of the drug and its metabolites was almost totally through the kidney. Low levels of unchanged drug were present in plasma and urine. PE mononitrate was the major drug metabolite in plasma and urine. Glucuronides of PE trinitrate, dinitrate, and mononitrate were identified for the first time in man. PE trinitrate glucuronide appeared in plasma rapidly and about 8% of the dose was excreted in urine. Reversible and irreversible pathways are proposed for the formation of the metabolites. The reconversion of PE trinitrate glucuronide to PE trinitrate is postulated to explain the duration of drug activity and excretion.

Oxisuran metabolism in pigs.

The fate of oxisuran in the pig was studied with 14C-labeled drug to quantify its biotransformation and disposition. Despite interanimal differences, it was clear that the compound absorbed rapidly and biotransformed extensively to metabolites which were excreted principally in urine rather than in feces. Direct attacks upon oxisuran involved reduction to diastereo-isomeric oxisuran alcohol sulfoxides and oxidation to oxisuran sulfone. Subsequently, the oxisuran alcohol sulfoxides were reduced to a sulfide and oxidized to a sulfone. Phase II reactions appeared to be limited to sulfation of oxisuran alcohol sulfoxides and oxisuran alcohol sulfone. Pharmacokinetics were investigated for oxisuran and its metabolites.

Metabolism of 3-(hydroxymethyl)-8-methoxychromone in the rat. I. Absorption, tissue distribution and excretion.

1. Two 14C-labelled preparations of 3-(hydroxymethyl)-8-methoxychromone were used to study the absorption, tissue distribution and excretion of isotope after oral administration to rats (20 mg/kg). 2. 14C, presumably from the labelled hydroxymethyl side-chain, was eliminated extensively as 14CO2. This excretion was triphasic; kinetic constants were calculated for each phase. 3. The major excretion route was via the kidney although significant quantities of isotope were excreted with the faeces. Isotope did not accumulate in tissues.

Oxisuran metabolism in the monkey.

Oxisuran metabolism was studied in the Rhesus monkey in order to assess the suitability of this species as an immunological model for man. The biotransformation pathways observed in the monkey are the same as those seen in rats and dogs. These pathways include the oxidation of oxisuran to a sulfone not found in human plasma or urine. Nevertheless, the monkey may merit immunological evaluation because the half-lives of biotransformation and elimination, although shorter than those exhibited by man, are greater than those in dogs and rats.

Metabolism of 3-(hydroxymethyl)-8-methoxychromone in the rat. II. Classification and identification of urinary drug metabolites.

1. Five metabolites were isolated from the urine of dogs dosed with 3-(hydroxymethyl)-8-methoxy[4-14C]chromone. These were identified as 8-methoxychromone, 2-hydroxy-3-methoxyacetophenone, 3-(hydroxymethyl)-8-hydroxychromone, 8-hydroxychromone and 2,3-dihydroxyacetophenone. 2. These compounds were also present in the urine of rats treated with labelled drug, together with unchanged drug and two intermediate metabolites, 3-carboxy-8-methoxychromone and 3-(carboxymethyl)-8-hydroxychromone. 3. In addition to the unconjugated labelled compounds, glucuronides and sulphates were identified. 4. Quantitative data were obtained for all of the 20 labelled compounds in rat urine. 5. A scheme is presented for the biotransformation of 3-(hydroxymethyl)-8-methoxychromone in rats and dogs, and a mechanism for scission of the gamma-pyrone ring is suggested.

3-(Hydroxymethyl)-8-methoxychromone and unconjugated metabolites in rat plasma. Identification of the biologically active species.

After administering 14C-labeled 3-(hydroxymethyl)-8-methoxychromone to rats by gavage, plasma was found to contain unchanged compound and three unconjugated metabolites. These metabolites were identified as 3-carboxy-8-methoxychromone, 8-methoxychromone, and 2-hydroxy-3-methoxyactophenone. The plasma levels of all four labeled compounds were determined from 30 min to 48 hr after drug administration. Only the levels of 3-(hydroxymethyl)-8-methoxychromone and 3-carboxy-8-methoxychromone correlated with the expression of antiallergy activity in the rat, and only these compounds were found to be active in vivo. However, a test system for the inhibition of anaphylactic histamine release in vitro showed activity only for 3-carboxy-8-methoxychromone.