The metabolic fate of the synthetic prostaglandin cloprostenol ('Estrumate') in the cow: use of ion cluster techniques to facilitate metabolite identification.

The metabolic fate of the synthetic prostaglandin cloprostenol ('Estrumate') in the cow has been studied. Following intramuscular administration of 0.5 mg and 10 mg of [14C]cloprostenol to cows urinary excretion accounted for 58.2% and 56.3% of the dose respectively. Unchanged cloprostenol and its tetranor acid, probably formed by beta-oxidation, were the major components identified in urine. The tetranor acid was also present as a glucuronide conjugate. This synthetic prostaglandin analogue is apparently a poor substrate for the enzymes 15-hydroxyprostaglandin dehydrogenase and 13,14-reductase, which are responsible for the rapid metabolic deactivation of endogenous prostaglandins, as no components identified in urine were found to have undergone metabolic attack at the C-15 atom in the cloprostenol molecule.

The disposition of the synthetic prostaglandin analogue cloprostenol ('Estrumate') in the rat and marmoset.

1. Following subcutaneous administration of the synthetic prostaglandin analogue [14C]cloprostenol to the rat (200 micrograms/kg), the dose was quantitatively recovered from the excreta: 52% of the dose was present in the urine and 43% in faeces. After intravaginal administration (200 micrograms/kg) 42% of the dose was recovered from the excreta, equally divided between urine and faeces, and 40% (range 25--66%) of the dose was recovered from the site of application. The radiolabelled compounds present in faeces were eliminated initially via the bile. 2. The max. observed plasma concn. of total 14C in the rat was 84 ng equiv./ml at 30 min after subcutaneous administration of cloprostenol (200 micrograms/kg). A component which co-chromatographed with cloprostenol on t.l.c. was rapidly cleared from plasma with a half-life of 54 min. After intravaginal administration of cloprostenol (200 micrograms/kg), low and persistent plasma concn. of 14C were detected. 3. The metabolic fate of cloprostenol in the rat and marmoset has been studied with radiolabelled and non-labelled drug mixed such that fragments detected by mass spectrometry exhibited characteristic 12C:14C isotope clusters. Metabolites derived from cloprostenol contained these characteristic doublets. 4. In the rat cloprostenol is metabolized by beta-oxidation to tetranor-cloprostenol. Unchanged cloprostenol and a conjugate of tetranor-cloprostenol were minor urinary metabolites. In the rat biotransformation of cloprostenol in the cyclopentane ring occurred; the tetranor acid of 9-keto-cloprostenol was identified in urine. In the marmoset unchanged cloprostenol and dinor-cloprostenol were major urinary components.

The disposition and metabolism of I.C.I. 58,834 (viloxazine) in animals.

1. 2-(2-Ethoxyphenoxymethyl-2,3,5,6-tetrahydro-1,4-oxazine (I.C.I. 58,834) has been prepared in three different 14C-labelled forms and its absorption, distribution, metabolism and elimination studied in six animals species. 2. In all species I.C.I. 58,834 was well absorbed after oral administration and extensively metabolized. Excretion via the kidney was the main route of elimination. 3. In the rat the major metabolic pathway is o-dealkylation and sulphate conjugation; the dealkylated metabolite was detected in brain extracts. A novel type of polar metabolite was isolated from rat urine, apparently a conjugate with sulphate and hippurate. 4. The metabolic pathways in beagle dogs include hydroxylation of the phenyl ring (and subsequent conjugation), N-methylation, formation of the N-methyl-N-oxide, and oxidation of the oxazine ring. 5. Maximum blood levels of I.C.I. 58,834 in dogs were unchanged during eight weeks daily administration and the half-life was 2.5-3 h. I.C.I. 58,834 is the main component in dog blood. Rat serum contains mainly conjugates of dealkylated I.C.I. 58,834 and the parent compound is a minor component. 6. None of the metabolites has significant CNS activity and activity observed following administration of I.C.I. 58,834 is due primarily to the parent compound.

Propofol metabolism in man during the anhepatic and reperfusion phases of liver transplantation.

1. An i.v. dose of 14C-propofol (0.53 mg/kg) was administered to three male and three female patients during the anhepatic phase of liver transplantation, which lasted 30-56 min after dosing. Arterial and venous blood samples, bile (T-tube drainage) and urine were collected at various times afterwards and submitted to h.p.l.c. and radioassay or specific fluorescence detection for the unchanged drug. 2. Extrahepatic metabolism was apparent during the anhepatic phase, since at 30 min post-dose, unchanged propofol comprised only 42-89% of the blood radioactivity. 3. Examination of the plasma radioactivity during the anhepatic phase in two subjects showed evidence of propofol glucuronide and 4-quinol sulphate, confirming extrahepatic metabolism of the drug. Quinol glucuronides were only detected in the liver reperfusion phase. 4. There was no evidence that the lungs contribute to the extrahepatic metabolism of propofol, since drug concentrations in the arterial blood were not less than in central venous samples. 5. During the first 24 h period, urine collected from five patients contained 7-74% dose, whilst the bile contained 0.1-0.9%. In three patients with normal renal function recovery in urine was 66-74% dose. Examination of urinary radioactivity in one subject showed the main component to be propofol glucuronide during the anhepatic phase.

The metabolism of ICI 118,587, a partial agonist of beta 1-adrenoceptors, in mice, rats, rabbits, dogs, and humans.

The absorption, metabolism, and excretion of 14C-labeled xamoterol (ICI 118,587) has been examined in mice, rats, rabbits, dogs, and humans. There was incomplete absorption by all species after oral administration, ranging from 9% by humans to 36% by dogs. Most of the absorbed radioactivity was eliminated within 24 hr of administration and the renal route predominated. Conjugates of the parent compound were the only observed metabolites in urine, the phenolic glucuronide being the principal animal metabolite and the phenol sulfate being the only human metabolite. There were marked interspecies variations in metabolite patterns and dogs were the only animal species in which the sulfate metabolite was detected. Comparison of the urinary metabolite patterns also showed higher output of the conjugates after oral administration than after intravenous administration, indicating that first pass metabolism was taking place. Little significant change in absorption or metabolism was seen over a range of oral doses; in rats, some saturation of the glucuronide-conjugating mechanism was observed but the sulfate-conjugating mechanism showed little, if any, diminished capacity at high dose levels in dogs. The use of fast atom bombardment mass spectroscopy for the determination of the molecular weight of conjugates is described.