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Biomedical subjects

I C Shaw

Publications and source records attributed to I C Shaw.

At least 55 records · Page 3Linked to original sources
PubMed1984

The prevention by (+)-Cyanidanol-3 of hepatitis-induced changes in the disposition of imipramine in the rat.

The administration of (+)-Cyanidanol-3 [+)-catechin) to the rat using a subchronic dosing regime based on that currently used in the therapy of acute viral hepatitis in man, largely prevented the changes in the disposition of a single dose of [14C]imipramine hydrochloride induced by the hepatotoxin, D-(+)-galactosamine hydrochloride in rats. Complete return to normal pharmacokinetics was not attained due to interaction between (+)-Cyanidanol-3 and imipramine. Biliary excretion of imipramine metabolites was 79.3% of the dose in control rats. This was reduced to 69.3 and 39.8% by the separate administration of (+)-catechin and galactosamine respectively. Concurrent administration of (+)-Cyanidanol-3 and galactosamine resulted in 64.8% of the imipramine dose appearing in bile. These results were reflected in changes in faecal and renal excretion of imipramine metabolites in surgically unmodified rats in which galactosamine injection caused an elevation of urinary excretion from 31.0 to 69.8% of the imipramine dose. Concurrent Cyanidanol administration reduced the effect of galactosamine so that only 46.9% was excreted in urine. These changes were due to decreased biliary excretion and increased renal excretion of the glucuronide conjugates of 2-hydroxyimipramine, 2-hydroxydesmethylimipramine and 10-hydroxyimipramine. None of the treatments used impaired the overall ability of the rat to metabolize imipramine, although the plasma clearance of imipramine was reduced by 42% as a result of galactosamine administration and by 21% during treatment with (+)-catechin alone or combined catechin and galactosamine treatment.

Animals↗
PubMed1984

The metabolism and excretion of [14C]imipramine in an experimental hepatitis.

The effect of experimental hepatitis, induced by i.p. D-galactosamine, on the metabolism and excretion of [14C]imipramine in the rat is reported. The major consequence was an increase of the conjugated metabolites of imipramine excreted in urine, resulting in a four-fold increase in 2-hydroxyimipramine glucuronide and two-fold increases in 2-hydroxydesmethylimipramine glucuronide and 10-hydroxyimipramine glucuronide. The total excretion of 14C-labelled metabolites in urine of galactosamine-treated rats was 69% dose compared with 37% in untreated animals. Faecal excretion of [14C]imipramine metabolites was lowered from 68% dose in untreated animals to 27% in animals with induced hepatitis. Induction of a galactosamine hepatitis decreased markedly the biliary excretion of imipramine metabolites in bile duct-cannulated rats; 80% dose was excreted in bile in normal rats, and 35.5% in rats with hepatitis. Plasma clearance of imipramine, after i.v. dosage, was decreased by 60% and clearance of metabolites (excluding imipramine) by 40%, in galactosamine hepatitis; the pharmacokinetics changed from a two- to a single-compartment system reflecting decreased extraction and/or metabolism, by the liver. The clinical implications of these findings are discussed in relation to the hazard attending the use of imipramine in patients suffering from liver disease.

Animals↗
PubMed1983

Decreased plasma half-life of cyclophosphamide during repeated high-dose administration.

Cyclophosphamide was given as IV doses of 50 mg/kg/day on each of four successive days as treatment for ovarian and lung cancer. Blood samples were taken at regular intervals and analysed for cyclophosphamide by gas liquid chromatography. The plasma half-lives (t 1/2) and volumes of distribution (V D) were calculated for each of the treatment days; t 1/2 was found to decrease with subsequent doses whereas V D was not significantly changed.

Cyclophosphamide↗
PubMed1983

2-Chloroacetaldehyde: a metabolite of cyclophosphamide in the rat.

Chloroacetaldehyde has been shown to be a urinary metabolite of cyclophosphamide in the rat. It was identified in the urine of rats given a mixture of [ring C-4, 14C]-cyclophosphamide and [chloroethyl-3H]-cyclophosphamide as its 2,4-dinitrophenyl-hydrazone derivative by its 3H label and by its co-chromatography with chemically synthesised chloroacetaldehyde. The reaction of chloroacetaldehyde with another urinary metabolite of cyclophosphamide is discussed and a nornitrogen mustard adduct postulated. The toxicity of chloroacetaldehyde is also discussed particularly in relation to the urinary bladder.

Acetaldehyde↗
PubMed1983

2-Chloroacetaldehyde, a metabolite of cyclophosphamide in the rat.

Following simultaneous i.v. administration of a mixture of [4-14C]cyclophosphamide (14C-CP) and [side-chain 3H]CP to rats, a metabolite containing predominantly 3H radioactivity was excreted in the urine. The 3H-labelled urinary metabolite was identified as 2-chloroacetaldehyde. Chloro[3H]acetaldehyde accounted for approx. 3.8% of urinary 3H radioactivity. The importance of chloroacetaldehyde as a toxic metabolite of CP is discussed, particularly in relation to haemorrhagic bladder disease.

Acetaldehyde↗
PubMed1982

Metabolism and excretion of the liver-protective agent (+)-catechin in experimental hepatitis.

1. Following oral administration of [U-14C](+)-catechin to rats with galactosamine-hepatitis, the biliary and faecal elimination of (+)-catechin metabolites was decreased compared with that in normal animals, Renal excretion of (+)-catechin metabolites was enhanced in galactosamine-hepatitis. 2. Although the biliary metabolites were present in similar proportions in galactosamine-hepatitis animals and controls, the major urinary metabolite, 3'-O-methyl (+)-catechin sulphate, was markedly decreased whereas 3'-O-methyl(+)-catechin glucuronide was increased by over 100%. 3. The total overall excretion of 3'-O-methyl (+)-catechin conjugates in rats with galactosamine-hepatitis was similar to that in normal animals indicating that catechol-O-methyltransferase activity is not significantly depressed in galactosamine-hepatitis. 4. Clearance of radioactivity from the blood following i.v. administration of [U-14C]-(+)-catechin was prolonged in galactosamine-hepatitis. 5. Liver perfusion experiments demonstrated depressed glucuronylation of (+)-catechin metabolites in galactosamine-hepatitis, whereas in liver homogenates synthesis of glucuronide conjugates of (+)-catechin metabolites was enhanced. 6. Lung slices were able to metabolize (+)-catechin and the lung is proposed as an extrahepatic site of (+)-catechin metabolism of increased importance in galactosamine-hepatitis. 7. The effects of galactosamine-hepatitis upon the structure of the hepatocyte plasma membrane are discussed in relation to decreased biliary excretion and glucuronylation.

Alanine Transaminase↗
PubMed1980

Identification of the major biliary metabolite of (+)-catechin in the rat.

1. Following oral administration of [U-14C]-(+)-catechin to the rat, the major biliary metabolite was shown to be the glucuronide of 3'-O-methyl-(+) catechin by chromatography and mass spectrometry. 2. [methyl-14C]-O-Methyl-(+)-catechin was formed by incubation of (+)-catechin with S-adenosyl-L-[methyl-14C]methionine in vitro in both liver homogenates and in the presence of purified catechol-O-methyl transferase. 3. Alkaline micro-fusion techniques have been used to determine the position of the O-methyl substituent in the B-ring of the isolated O-methyl-(+)-catechin glucuronide.

Animals↗
PubMedDate not supplied

A surprising case of endrin poisoning in dogs.

A case of possible malicious poisoning of dogs by endrin was investigated. A variety of tissues were analysed. The stomach contents of one dog contained 5 g/kg endrin. The results are compared with recorded data from feeding studies pursued elsewhere to aid the diagnosis of dieldrin and endrin intoxication. A number of organochlorine compounds closely related chemically to endrin were tentatively identified.

Animals↗
PubMedDate not supplied

Depletion of protein-bound furazolidone metabolites containing the 3-amino-2-oxazolidinone side-chain from liver, kidney and muscle tissues from pigs.

Ten 3-month-old pigs were treated with feed containing 300 mg furazolidone per kg for a period of 7 days, followed by withdrawal periods of 0, 1, 2, 3 or 4 weeks (two per group). The treatment resulted in the formation of protein-bound metabolites containing an intact 3-amino-2-oxazolidinone (AOZ) side-chain that could be chemically released and then detected in liver, kidney and rump muscle tissues even 4 weeks after dosing. In tissues from animals killed at the end of the medication period, 993, 600 and 124 ng of AOZ were released from 1 g of liver, kidney and muscle respectively. In the tissues of the animals killed after a further 4 weeks the corresponding levels were 41, 7 and 10 ng/g respectively. It may be concluded that long withdrawal periods prior to slaughter for human consumption are required for pigs treated with furazolidone, because of the long residence time of protein-bound AOZ and the possibility that it might be released from its protein-bound form in the stomach and subsequently be transformed into a hydrazine.

Animals↗