K. W. Woodhouse

Effects of age and gender on in vitro properties of human liver microsomal monooxygenases

Aging in humans is associated with marked declines in the disposition of numerous drugs and other xenobiotics that require hepatic biotransformation before elimination. Considerable pharmacokinetic evidence in humans, coupled with data on in vitro liver microsomal monooxygenase functions generated in inbred male rodent models, has implicated impaired liver phase I drug metabolism (i.e., diminished efficacy of microsomal monooxygenases) in reduced drug clearance in the elderly. This study (1) assessed the in vitro activities and amounts of liver microsomal monooxygenases as a function of donor age and gender in healthy humans and (2) provides the most extensive and comprehensive data to date demonstrating the absence of significant age‐ and gender‐dependent differences in the activities and contents of human liver monooxygenases.

Age and self-poisoning: the epidemiology in Newcastle upon Tyne in the 1980s

The epidemiology of 737 consecutive self-poisoning admissions to Freeman Hospital, Newcastle upon Tyne, has been investigated with reference to age in young (< 35), mid-aged (35-64) and elderly (≥ 65 year) patients. The most important differences were increased formal psychiatric illness in the elderly, demonstrated by increased likelihood of admission to psychiatric units; less likelihood of overdose with multiple agents in the elderly, and less use of alcohol. There were also differences in the types of drugs used. The youngest patients took more paracetamol and less psychoactive drugs and more of their drugs were prescribed for a relative than the other two groups. The elderly were much less likely to receive gastric lavage or emesis and more likely to receive supportive treatment only than younger patients. This difference may, in part, be explained by the more frequent occurrence of benzodiazepine poisoning in those over 65 years.

The effect of alcoholic cirrhosis on the two kinetic components (high and low affinity) of the microsomal 0-deethylation of 7-ethoxycoumarin in human liver

Summary1. The activities of the two kinetic components (high and low affinity) of the microsomal 0-deethylation of 7-ethoxycoumarin have been measured in liver from patients with alcoholic cirrhosis and in normals. 2. The activity (expressed as pmol 7-OH coumarin formed/mg microsomal protein/min) of both components of the enzyme was significantly lower in alcoholic cirrhosis (high affinity=3.27±1.18, low affinity 60.9±11.6) than in normals (high affinity 9.43±2.37, low affinity 111.3±9.2). 3. These results are further evidence that there is a broad impairment of hepatic microsomal mono-oxygenase activity in alcoholic cirrhosis.

Is diurnal variation in absorption of slow-release aminophylline an age-related phenomenon?

SummaryTo specifically assess the possible influence of ageing on the changes in theophylline absorption, the plasma concentration-time profiles of sustained-release aminophylline were studied in 8 young and 8 elderly subjects after 9 a.m. and 9 p.m. administration.After 9 p.m. administration, in elderly subjects, maximum plasma theophylline concentrations (Cmax) were decreased, time to maximum concentration (tmax) was increased, and area under plasma concentration-time curve (AUC) was decreased compared to 9 a.m. dosing. This was true for single dose and at steady-state and suggests delayed and diminished absorption at night. No statistically significant changes were seen in the young subjects.This study therefore suggests that time related changes in absorption may be more significant in elderly subjects, possibly due to postural differences after 9 p.m. dosing, and this should be borne in mind when prescribing.

7-Ethoxyresorufin deethylase (EROD) in human liver —The effect of alcoholic liver disease

SummaryWe have investigated the effect of alcoholic liver disease (ALD) on the metabolism of 7-ethoxycoumarin 0-deethylase in human liver microsomes. EROD activity was significantly reduced in tissue from ALD patients who smoked, compared to smoking controls. A similar trend was seen in non-smokers. These results have implications for the metabolism of environmental carcinogens.

2,5-diphenyloxazole as a probe for microsomal mono-oxygenation in human and rat liver

2,5-Diphenyloxazole (PPO) is metabolized to one major fluorescent product by human liver and rat liver microsomes. PPO metabolism by human-liver microsomes involves more than one cytochrome P-450 isozyme, termed low-affinity and high-affinity components. At a substrate concentration of 0.1 microM, 95% of activity is due to the high-affinity component whereas at 100 microM 69% of activity is due to the low-affinity component. Inhibition studies with metyrapone and alpha-naphthoflavone at 0.1 microM and 100 microM suggest that the high-affinity component may reflect a 3-methylcholanthrene-inducible form of cytochrome. Therefore studies at low substrate concentrations may be a useful tool for cytochrome P-450 studies in man. Rat liver microsomes show linear kinetics indicating the involvement of one major form of cytochrome P-450.