Malcolm C. Crew

The absorption and biotransformation of glyceryl trinitrate-1,3-14C by rats

Abstract The metabolism of 14 C-labeled glyceryl trinitrate was studied in the rat. Absorption, tissue distribution and elimination were followed after administering a single dose by gavage. Thin-layer chromatography and radio-scanning methods were employed to assay urinary drug metabolites, including the isomeric glyceryl dinitrates and glyceryl monoitrates. It was found that glyceryl trinitrate was absorbed and transformed very rapidly. The major products were carbon dioxide, urinary glycerol, glyceryl nitrates, organic acids and some unidentified tissue components which were also labeled with 14 C.

Biliary excretion and biotransformation of pentaerythritol trinitrate in rats

Abstract A study was made of the biliary excretion of 14 C-pentaerythritol trinitrate in the rat to elucidate the possible role of enterohepatic circulation in the prolonged action of the drug. The biliary drug excretion consisted entirely of metabolites which were previously unknown, namely, the glucuronides of pentaerythritol mononitrate, dinitrate and trinitrate. Drug radioactivity entered the bile faster after intravenous than after oral dosing. This difference (51% vs. 30% of the dose in 4 hr) was entirely due to pentaerythritol dinitrate glucuronide; the pentaerythritol trinitrate glucuronide level was approximately the same (9.5% of the dose in 4 hr). Enterohepatic circulation was indicated by the observation that 2.5 times more drug radioactivity was excreted into the urine by intact rats than by biliary cannulated rats. A comparison of the biliary and urinary excretion products of pentaerythritol trinitrate suggests that the enterohepatic circulation provides the opportunity for gastrointestinal resorption and recirculation of the free drug.

Correlation of analgesia with levels of tilidine and a biologically active metabolite in rat plasma and brain

Abstract The analgesic ED 50 of tilidine administered orally to rats was 15.4 mg/kg at 15 min and 17.2 mg/kg at 30 min. The drug was metabolized quickly and extensively, and it and its principal metabolite readily crossed the blood-brain barrier. Analgesia after the oral administration of tilidine fumarate to rats was correlated with levels of this metabolite in plasma and brain, and with the tilidine levels in plasma. It appears probable that the conversion of tilidine into its metabolite. which has analgesic properties, is closely related to the analgesic state.

Metabolism of Oxisuran, an Immunosuppressant, by the Rat

1. The pharmacodynamics and biotransformation of oxisuran were studied in rats, a species in which the drug has immunosuppressive activity. Orally administered [14C]oxisuran was absorbed rapidly and produced max. blood radioactivity concentrations over the period from 0.5 to 3 h. Probably influenced by enterohepatic circulation, the 14C blood level declined gradually with a half-time of approx. 10 h. Renal excretion was the principal route of elimination for the drug and its metabolites.2. The metabolism of oxisuran involved oxidation and reduction as phase 1 reactions. The minor pathway involved oxidation of oxisuran to its sulphone and reduction of this ketone sulphone to the corresponding alcohol sulphone. The major pathway involved reduction followed by oxidation to form the same end product.3. The reduction of oxisuran to its alcohol created a second asymmetric centre and yielded two isomers which were resolved by g.l.c. The four metabolites were identified by t.l.c., elemental analyses and autoradio...

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.

Disposition and Biotransformation of 14C-Oxisuran in the Dog

1. The absorption, excretion and biotransformation of 14C-labelled 2-[(methylsulphinyl)acetyl] pyridine (oxisuran) was studied in the dog.2. The compound was absorbed readily, established high blood levels of radioactivity and was excreted predominantly in the urine.3. Three urinary drug metabolites were identified and their structures established that oxisuran was subjected to both reductive and oxidative conversions.4. The major metabolic pathway involved reduction of the carbonyl group followed by oxidation of the sulphoxide group : oxisuran α-(methylsulphinyl)-methyl-2-pyridinemethanol α-(methylsulphonyl)methyl-2-pyridine-methanol.5. Oxidation preceded reduction in the minor metabolic sequence and yielded the same end product via 2-(methylsulphonyl)acetyl pyridine.

Studies on the metabolism in man of oxisuran, a differential immunosuppressive drug

Two groups of normal human volunteers received 14C‐labeled oxisuran orally in doses of 0.5 gm or 1.0 gm. The compound reached peak plasma levels in 1 to 2 hours, indicating rapid absorption from the gastrointestinal tract. Oxisuran and its metabolites were excreted almost completely by the kidney. Oxisuran, two isomeric oxisuran alcohols, and oxisuran alcohol sulfone were identified in plasma and urine. The plasma half‐lifes were approximately 1.2 hours for oxisuran, 15 hours for the oxisuran alcohols, and 60 hours for oxisuran alcohol sulfone. Urinary half‐lifes of these maior metabolites were almost identical to their plasma half‐lifes. Low levels of unidentified polar and nonpolar metabolites were found in plasma and urine, and their half‐lifes was estimated. A model of oxisuran metabolism in man was developed trom these pharmacodynamic studies.

Comparative Metabolism of Oxolinic Acid by the Rat, Rabbit and Dog

1. The metabolism of oxolinic acid was studied in rats, rabbits and dogs after the oral administration of 10 mg/kg of the 14C-labelled drug. Within 24 h, 18% of the radioactivity had been excreted in the urine from the dog, 27% from the rat and 49% from the rabbit. The faecal radioactivity was 14% from the dog, 35% from the rabbit and 41% from the rat.2. Small amounts of unconjugated oxolinic acid were found in the urine of all the species as a polar complex. The amount of this complex was much smaller from the dog (0.3%) than from the other species (2–6%). The rabbit excreted far more oxolinic acid glucuronide (14.5%) than did the other species (1.5%).3. Small amounts of 1-ethyl-1,4-dihydro-7-hydroxy-6-methoxy-4-oxoquino-line-3-carboxylic acid (1–6%) were also found in the urine of every species. In every case one-third to one-fifth of this metabolite was unconjugated, with the remainder excreted as the glucuronide.4. There was no evidence for the metabolic removal of the ethyl side chain of oxolinic acid.

Pentaerythritol trinitrate metabolism by the rat.

Abstract Rats were studied after being given a single dose of 14C-pentaerythritol trinitrate by gavage. The labeled components of the blood, urine and gastrointestinal tract were identified by thin-layer chromatography and assayed quantitatively by radioscanning. Pentaerythritol trinitrate was found to be absorbed and excreted rapidly by the rat. The drug metabolites were pentaerythritol, pentaerythritol mononitrate and pentaerythritol dinitrate. Comparisons of the data with the results of similar studies with pentaerythritol tetranitrate (PETN) and nitroglycerin showed that pentaerythritol trinitrate was absorbed much faster than PETN and almost as quickly as nitroglycerin, and that the urinary excretion of pentaerythritol trinitrate proceeded at the highest rate. Additionally, pentaerythritol trinitrate was the only one of the three drugs which passed intact into the urine.

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.