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Biomedical subjects

J R Idle

Publications and source records attributed to J R Idle.

At least 109 records · Page 6Linked to original sources
PubMed1991

Comparative effects of the diastereoisomers, quinine and quinidine in producing phenocopy debrisoquine poor metabolisers (PMs) in healthy volunteers.

1. A single oral dose (50 mg) of quinidine significantly increased the debrisoquine metabolic ratio in six healthy volunteers. For four of the volunteers the metabolic ratio changed to that typical of the poor metaboliser (PM) phenotype. 2. The effect of quinidine in producing debrisoquine oxidation "poor metaboliser" phenocopies persisted for at least 3 days but had disappeared by 1 week. 3. The debrisoquine metabolic ratios for the same six subjects were not significantly altered by the oral administration of quinine (200 or 400 mg), the diastereoisomer of quinidine. 4. The plasma pharmacokinetic parameters of both nortriptyline and desipramine in healthy volunteers were all changed to those more typical of the debrisoquine PM phenotype following the concomitant administration of quinidine (50 mg). 5. It is concluded that quinidine, but not its diastereoisomer quinine, is a potent selective inhibitor of the in vivo oxidation of debrisoquine and can produce an artifactual PM phenocopy in persons who are phenotypically extensive metaboliser (EM) phenotype status. The clinical implications of this observation are discussed.

Adult↗
PubMed1991

Is environmental carcinogenesis modulated by host polymorphism?

It is now clear that tobacco smoking, alcohol consumption, dietary factors and occupation can all interact with genetic host factors to place one individual at a greater or lesser risk of a particular cancer than another. Phenotypes which confer significantly elevated risks arise from the human CYP1A1. CYP2D6, GST1 and NAT (N-acetyltransferase) genes. The last is the only one remaining to be cloned. It is envisaged that several of these genes may interact in a given circumstance cooperatively to increase susceptibility. For example CYP1A1, CYP2D6 and GST1 genotypes may have additive or multiplicative risks of bronchogenic carcinoma in cigarette smokers. CYP2D6 and NAT genotypes may interact in bladder cancer. The advent of molecular genetics brings us closer to the day when, for example, factory workers in potentially hazardous environments might be screened using PCR methodology on skin scrapings or buccal swabs for their innate susceptibility to combined workplace and lifestyle cancer risks.

Aryl Hydrocarbon Hydroxylases↗
PubMed1991

Genetic and metabolic criteria for the assignment of debrisoquine 4-hydroxylation (cytochrome P4502D6) phenotypes.

A randomly selected population of 73 volunteers, together with 22 previously established poor metabolisers of debrisoquine, were phenotyped for their ability to 4-hydroxylate debrisoquine and were also analysed for a number of mutations in the CYP2D6 gene. Genotyping was performed using both restriction fragment length polymorphism with the restriction enzyme Xba I, together with two separate polymerase chain reaction assays. Together, these assays detected 98% of mutant alleles in the poor metaboliser group which corresponded to positive identification of 95% of this group. The most common mutant allele detected as the 29B which comprised 75% of total alleles in the poor metaboliser group, whereas the 29A had a frequency of 0.11. Two other allelic variants, which were detectable by restriction fragment length polymorphism analysis occurred at frequencies of 0.07 and 0.05. In the volunteer group, 2.7% of subjects were genotypically poor metabolisers, 35.6% heterozygous extensive metabolisers and 61.7% homozygous extensive metabolisers, on the basis of the genotyping assays used. A good correlation between debrisoquine metabolic ratio and genotype was obtained particularly for subjects genotyped as homozygous extensive metabolisers.

Alleles↗
PubMed1991

Genetic predisposition to Balkan endemic nephropathy: ability to hydroxylate debrisoquine as a host risk factor.

The objective of this study was to examine the association between efficiency of oxidative metabolism and risk for developing Balkan endemic nephropathy (BEN) and/or transitional-cell carcinoma of the urinary tract, using a case-control design controlling for age, gender and socioeconomic factors. Over 900 urine samples were taken from 646 subjects, divided into the following groups: healthy subjects from areas with no BEN; healthy subjects from villages with BEN; subjects suspected of having BEN; and subjects with BEN and/or upper urinary tract tumours (UUT). BEN patients and controls from the same villages were of similar age. The highest urinary recovery of debrisoquine was found among controls from areas with no BEN; recovery in BEN patients was only 50% of that in controls. The most interesting result is that BEN patients did not have impaired debrisoquine metabolism: subjects who metabolized less than 25% of the drug represented only 2.9% of BEN patients, 12.4% of controls from BEN villages and 12.7% of controls from outside the BEN area. The very poor metabolizers represented 1.0% of BEN patients and 4.8-5.8% of controls. the percentages of extensive metabolizers in the same groups were 86.3, 64.5 and 67.4%, respectively. The mean metabolic ratio rose progressively from BEN patients less than suspected BEN patients less than controls from BEN villages less than controls from non-BEN villages; the maximum metabolic ratios were 40, 51, 72 and 87, respectively. The cumulative distribution of the 8-h urinary debrisoquine metabolic ratios, presented as a normal probability plot, formed a discrete population with values over 10. The distribution among patients with BEN/UUT indicates a predominance of extensive debrisoquine hydroxylation and a lack of poor metabolizers. These results are consistent with the hypothesis that the efficiency of oxidative metabolism is greater in BEN patients and that it may be one of the key host factors determining predisposition to these diseases.

Adult↗
PubMed1990

The effect of route of administration and fractionation of dose on the metabolism of ifosfamide.

The measurement of urinary ifosfamide, isophosphoramide mustard, dechloroethyl ifosfamide and carboxyifosfamide using high-performance thin-layer chromatography with photographic densitometry (TLC-PD) is described. This technique was also used to demonstrate the large inter-individual variation in the ifosfamide metabolic profile of patients receiving the drug as single-agent therapy for non-small-cell lung cancer. In addition, oral administration was shown to result in higher levels of these metabolites in the urine. Fractionation of the ifosfamide dose over several days resulted in increasing levels of metabolites in the urine, consistent with auto-induction of ifosfamide metabolism.

Administration, Oral↗
PubMed1990

Cytochrome P450dbl phenotypes in malignant and benign breast disease.

129 female patients with breast cancer and 79 controls undergoing biopsy for benign breast conditions had debrisoquine hydroxylator phenotype established. 129 female hospital patients with known hydroxylator phenotype were used as another control group. The breast cancer cases differed significantly from the benign controls in their debrisoquine phenotype, with 10% being poor metabolisers compared with none of the controls (P less than 0.01). However, while a comparison of the distributions of metabolic ratio (an inverse measure of debrisoquine metabolism) of breast cancer patients and hospital controls showed a significant difference by rank, there was no significant difference in the proportion of poor metabolisers in these two groups. The cases with benign disease differed from the hospital controls in both metabolic ratio distribution (P less than 0.001) and frequency of poor metabolisers (P less than 0.05). Although there was a shift in metabolic ratio distribution, debrisoquine hydroxylator phenotype was not a genetic marker for breast cancer. Why no patients undergoing biopsies for benign conditions were poor metabolisers is unknown.

Adult↗
PubMed1990

Lack of effect of co-trimoxazole on the pharmacokinetics and pharmacodynamics of nifedipine.

The pharmacokinetics of nifedipine and its primary oxidised metabolite, M-I were studied in nine healthy volunteers following a single oral dose of 20 mg nifedipine alone or after pretreatment with oral co-trimoxazole. Following pretreatment with co-trimoxazole, no significant effect was detected on maximum plasma concentration, elimination half-life, or area under the plasma concentration-time curve of either nifedipine or M-I, nor on the blood pressure response to nifedipine.

Adult↗
PubMed1990

Pharmacokinetics and toxic effects of nifedipine in massive overdose.

A 57-year-old man took 30 x 20 mg nifedipine retarded release tablets. He developed hypotension, tachycardia and flushing, but remained in sinus rhythm. The concentration of nifedipine 10 h after overdose was 604 micrograms 1-1, and of the M-I metabolite 110 micrograms 1-1. Log concentration time curves were linear from 10-72 h for nifedipine, with a half-life of 7.5 h; and for M-I with a half-life of 8.2 h. On this evidence, oral absorption of nifedipine retarded release is complete by 10 h. There was no evidence of saturation of nifedipine or M-I metabolism, even at concentrations ten times above the therapeutic concentration.

Drug Overdose↗
PubMed1989

Trimethylaminuria: the detection of carriers using a trimethylamine load test.

A method potentially of value for investigating putative heterozygotes or carriers of trimethylaminuria by using a single oral dose of trimethylamine (TMA) is described. For healthy volunteers under normal dietary condition and following oral challenge with 300 mg and 600 mg TMA-base, over 90% of the urinary TMA was excreted in the form of TMA (93.6 +/- 1.6%). However, at a dose level of 900 mg TMA-base, there was clear evidence of saturation of the N-oxidation reaction as urinary TMA excretion declined to 77.2% (range 74.8-78.9) of the total dose of TMA. By contrast, in pedigree studies based upon propositi with trimethylaminuria, several parents were identified who showed clear evidence of saturation of the N-oxidation of TMA at the 600 mg TMA-base dose level, but not at 300 mg TMA-base or under normal dietary condition. In these individuals, the proportion of urinary TMA as trimethylamine N-oxide (TMAO) declined to (77.3 +/- 1.7%). Accordingly we propose that the oral administration of 600 mg TMA-base and the analysis of the following 0-8-h urine collection may be useful for the investigation of possible carriers of trimethylaminuria.

Administration, Oral↗
PubMed1989

The influence of food on the pharmacokinetics of 'biphasic' nifedipine at steady state in normal subjects.

Previous studies following single dose administration have suggested that the pharmacokinetics of various nifedipine formulations could be influenced by the timing of associated food consumption. In order more closely to reflect the clinical situation we have carried out a study at steady state using a 'biphasic' formulation comprising 'rapid' and 'retarded' drug release components. Fifteen normal subjects took 20 mg 'biphasic' nifedipine 12 hourly for 10 days. Studies were carried out on days 4, 7 and 10. On these days the nifedipine was taken 2 h or 1 h before or immediately following a light breakfast. A light breakfast influenced neither the rate nor the extent of nifedipine absorption nor the rate or extent of major metabolite appearance. We conclude that at steady state the timing of a light meal is unlikely to alter in any clinically important manner the pharmacokinetics of nifedipine released from 'biphasic' tablets.

Adult↗
PubMed1989

Variable metabolism of pinacidil: lack of correlation with the debrisoquine and trimethylamine C- and N-oxidative polymorphisms.

1. The urinary excretion of pinacidil and its N-oxide in man was found to vary over a five-fold range. 2. Studies in individuals with inherited deficiencies for C-hydroxylation (debrisoquine type) and trimethylamine N-oxidation showed that the N-oxidation of pinacidil did not co-segregate with these oxidative polymorphisms. 3. It is concluded that the variable N-oxidation of pinacidil is most likely to be due to variations in the activity of the P-450 isozymes rather than in the microsomal flavoprotein containing mixed-function amine oxidase of Ziegler which is considered to be responsible for the N-oxidation of trimethylamine.

Adult↗