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Biomedical subjects

J R Idle

Publications and source records attributed to J R Idle.

At least 163 records · Page 9Linked to original sources
PubMed1982

Metabolic oxidation of methaqualone in extensive and poor metabolisers of debrisoquine.

The metabolism of methaqualone to the glucuronides of 5 C-monohydroxy metabolites and to the N-oxide has been studied in 2 groups of healthy young adults phenotyped as extensive and poor metabolisers of debrisoquine. No significant interphenotype differences were observed with respect to the excretion of any of the 6 metabolites. It is probable that the genetic regulation of the pathways leading to these metabolites is at a locus other than that which is responsible for the regulation of the oxidation of debrisoquine, guanoxan, phenacetin, phenytoin and sparteine.

Adult↗
PubMed1982

Genetic polymorphism of phenformin 4-hydroxylation.

The ability to oxidize a single 50-mg dose of phenformin to its 4-hydroxy metabolite was determined in 195 individuals. Variations in the urinary ratio of phenformin/4-hydroxyphenformin ranged from 1 to 184. Family studies were consistent with the hypothesis that this variability resulted from a single gene mode of inheritance in which impaired hydroxylation of phenformin appears as an autosomal recessive trait. Both genotype frequencies and the degree of dominance of the extensive metabolizer phenotype over the recessive showed a remarkable resemblance to those described for debrisoquine 4-hydroxylation, which was confirmed by the high degree of correlation (rs=0.785, P less than 0.0001) between the phenformin ratio and the debrisoquine metabolic ratio. Such close agreement between the metabolism of these drugs may indicate that the same genetic control is in operation. Such genetic polymorphism of phenformin hydroxylation may have important implications for therapeutic response and for the possibility of toxic effects in a few individuals.

Adolescent↗
PubMed1982

The metabolism of [14C]cimetidine in man.

1. The excretion and metabolism of [2-(14)C]cimetidine (500 mg orally) was studied in five male volunteers. 2. Over 70% of the 14C was excreted in the urine after 24 h by all individuals with 5% in the faeces; 97% being recovered in total after three days. 3. Unchanged cimetidine was the largest urinary component (63%), followed by a polar conjugate tentatively identified as cimetidine N'-glucuronide (24%). Smaller amounts of the oxidized metabolites, cimetidine sulphoxide and 5-hydroxymethylcimetidine, together with the hydrolysis products, cimetidine guanylurea and cimetidine guanidine, were also observed. 4. Cimetidine and its sulphoxide were identified in faecal samples. Anaerobic incubations of cimetidine or cimetidine sulphoxide with faecal homogenates showed that reduction was the predominant reaction under these conditions. 5. Studies in one individual over a wide dose range (0.5 mg to 1.5 g orally) showed little variation in excretory profile or metabolic spectrum.

Administration, Oral↗
PubMed1982

Population studies of polymorphism in drug oxidation and its relevance to carcinogenesis.

Metabolic oxidation plays a central role in both the detoxication and chemical activation of many environmental procarcinogens. A plethora of in vitro data suggests that metabolic activation and subsequent DNA covalent binding of such substances vary widely between individuals. The need for a simple test in vivo of human variability in metabolic oxidation is apparent, not only to help understand the variation in disposition of many drugs and other chemicals, but also as an aid to predicting individual cancer risk from metabolically activated procarcinogens. Current methodology has failed to provide such information for a number of reasons, which are discussed. A genetic polymorphism affecting the metabolic disposition and biological effects of a number of drugs is described. Persons can be phenotyped as either extensive or poor metabolizers, using the drug debrisoquine. The measured variable, urinary 'metabolic ratio', which is distributed across these two phenotypes with values of 0.1 to 200, gives a clear indication of the metabolic behaviour of many drugs and, possibly therefore, of certain procarcinogens. Accordingly, two groups of cancer patients were investigated with debrisoquine, namely Nigerians with hepatocellular and related tumours and white smokers with bronchial carcinoma in the United Kingdom. These preliminary studies are suggestive of a phenotype component in relative cancer risk, poor metabolizers appearing to be less vulnerable. Animal model data seem to confirm a relationship between aflatoxin B1 metabolism and DNA binding and polymorphic debrisoquine oxidation. It is concluded that the biological consequences of ingesting exogenous chemicals may be better understood from studies of discrete, genetically determined steps in their interaction with living systems.

Animals↗
PubMed1981

Some observations on the oxidation phenotype status of Nigerian patients presenting with cancer.

The hypothesis is being explored that there may be an association between genetically determined oxidation status and propensity to develop carcinoma in response to environmental chemical carcinogens. For this purpose, the genetic structure of a normal, healthy Nigerian population with respect to oxidation status, has been compared with that found for a group of 59 Nigerian patients presenting with carcinoma of the liver and gastrointestinal tract. Genetically determined oxidation status was assessed by measuring the extent of oxidation of a probe drug, debrisoquine, to its major metabolite, 4-hydroxydebrisoquine. The cancer group contained a disproportionately large number of individuals who were extensive oxidizers compared to the controls (2 P = 0.0045). The findings support the view that genetically determined oxidation status may be an important host factor in influencing responsiveness to chemical carcinogens that require oxidative metabolic activation.

Adolescent↗
PubMed1981

Influence of DH/DL alleles regulating debrisoquine oxidation on phenytoin hydroxylation.

Eleven subjects of previously determined debrisoquine oxidation phenotype status (extensive metabolizer [EM], n = 5; poor metabolizer [PM], n = 6) were studied for their ability to perform the aromatic 4-hydroxylation of phenytoin. The PM subjects studied were found to be slower metabolizers of phenytoin than EM subjects in terms of the metabolite formation rate constant (kfHPPH: EM, 0.030 +/- .007 hr-1; PM, 0.016 +/- 0.003 hr-1, 2p less than 0.001) and cumulative excretion of 4-hydroxyphenytoin (48 hr after dosing: EM, 52.8 +/- 10.7%; PM, 36.9 +/- 7.0%, 2p less than 0.01). It is concluded that the metabolic oxidation of phenytoin is influenced by the same DH and DL alleles, acting at the same locus, that regulate the hydroxylation of debrisoquine and that impaired metabolism of phenytoin may be expected to occur in about 9% of the population, being transmitted as an autosomal-recessive trait. It is suggested that debrisoquine oxidation phenotyping may have predictive value in guiding phenytoin dosage, particularly in those with impaired oxidation.

Adult↗
PubMed1981

Animal modelling of human polymorphic drug oxidation--the metabolism of debrisoquine and phenacetin in rat inbred strains.

The metabolism of debrisoquine (5 mg kg-1 orally) was investigated in females of 7 strains of rat. Two major metabolic pathways, those of 4- and 6-hydroxylation were found to be polymorphic. The DA strain eliminated in urine only 7-10% of the dose as 4-hydroxy-debrisoquine together with 31-55% debrisoquine while the corresponding values for the Lewis strain were 44-55% and 11-17% respectively. Accordingly, DA and Lewis rats were proposed as models for the human PM (poor metabolizer) and EM (extensive metabolizer) drug oxidation phenotypes. To further test this model, DA and Lewis rats were given phenacetin (200 mg kg-1 orally). This underwent O-de-ethylation to paracetamol (52-55%) and aromatic 2-hydroxylation (7-8%) in Lewis rats. The corresponding findings in DA rats were 35-40% O-de-ethylation and 12-13% 2-hydroxylation. It is suggested that, with respect to both debrisoquine and phenacetin, Lewis and DA inbred rat strains afford a model of oxidative drug metabolism for the human EM and PM phenotypes respectively.

Animals↗
PubMed1981

Influence of the genetically controlled deficiency in debrisoquine hydroxylation on antipyrine metabolite formation.

The influence of the genetically controlled deficiency in debrisoquine hydroxylation on antipyrine metabolite formation was studied by giving 500 mg antipyrine to 14 extensive and 10 poor metabolizers of debrisoquine. The pharmacokinetics of antipyrine were determined on the basis of the saliva concentration time curve and the cumulative urinary excretion of 4-hydroxyantipyrine, norantipyrine, 3-hydroxymethyl-antipyrine, and 3-carboxyantipyrine was measured for 32 h following drug administration. Antipyrine elimination half-life, volume of distribution, and total clearance were almost equal for the two groups. Significant differences in the excretion of antipyrine metabolites were not observed, except for 3-hydroxymethyl-antipyrine which was excreted in poor metabolizers about 30% less than in extensive metabolizers (p less than 0.01). However, this difference only reached borderline significance (p less than 0.1) when clearance values for production of this metabolite were calculated. It is concluded that different species of the drug-oxidizing enzymes (cytochrome P-450 system) are involved in the metabolism of debrisoquine and antipyrine. Possibly the enzyme responsible for hydroxylating debrisoquine is partly involved in the formation of 3-hydroxymethyl-antipyrine.

Aging↗
PubMed1980

Toxicological implications of polymorphic drug metabolism.

The occurrence of genetic polymorphisms of drug metabolism means that populations contain subgroups (phenotypes) that differ sharply in their abilities to effect a number of metabolic reactions. Because of this, major interphenotype differences occur in responsiveness to drugs and toxic substances. The well established genetic polymorphisms of acetylation and hydrolysis illustrate the important association that exists between phenotype and propensity to develop toxic and exaggerated responses to some substances. Recently, for metabolic oxidation, a new genetic polymorphism of drug metabolism has been described and it promises to provide a better understanding of inter-individual variability in the metabolic handling of, and responsiveness to, drugs and toxic substances. The following effects of the polymorphism are described here: (a) its influence in determining variable presystemic metabolism and hence systemic drug availability; (b) its role in determining alternative toxic pathways of metabolism in individuals who have a genetically determined impairment of oxidative capacity and (c) its influence on the development of agranulocytosis associated with metiamide administration.

Alleles↗