Chapter One of this thesis concentrates on known age and sex effects on the disposition of drugs. It is well known that renal excretion of drugs decreases in the aged, more or less in parallel with decreasing renal function. Less is known of hepatic drug elimination in the aged. The main theme of this thesis has been to study the disposition of three different drugs, alcuronium, spironolactone and acetylsalicylic acid in the elderly population. Alcuronium is a non-depolarising muscle relaxant and is excreted mainly as unchanged drug in urine. Spironolactone is a potassium-sparing diuretic which undergoes a rapid dethioacetylation to the resulting canrenone in humans. Canrenone itself is an aldosterone antagonist. Acetylsalicylic acid is a minor analgesic which has saturable metabolic characteristics. The half-life of salicylate is dependent upon the body content of the drug and ranges from 3 to 20 hours. Limited capacities of the metabolic pathways converting salicylate to salicylurate and to salicyl phenolic glucuronide are responsible for the dose dependent kinetics.
Chapter Two describes the methodology and experimental design employed in this thesis. For each drug, patients of 65 years old or more were recruited as the elderly group for the study. The patients selected were free of any major pathological disorder likely to alter drug metabolism and all of them underwent routine biochemical screening to exclude significant renal and liver diseases. The respective drugs and their metabolites in biological fluids were measured by selective high performance liquid chromatography. The pharmacokinetic data obtained were analysed by both model-dependent and model-independent approaches.
Results and discussions of the above studies are included in Chapter Three and the relevant conclusions are summarized in Chapter Four. As predicted from the nature of the drug, alcuronium was found to have a prolonged half-life and a reduced clearance in the elderly. However, in elderly patients undergoing aortic aneurysm resection or total hip replacement, the values of pharmacokinetic parameters such as plasma clearance, elimination half-life and the apparent volume of distribution of the drug were found to be comparable to that of normal young patients. The differences between these two groups of elderly patients may be due to the intense care taken by the anaesthetist in maintaining control of cardiac output in the former group.
Plasma levels of canrenone and 'total metabolites' after base hydrolysis were compared in young and elderly subjects following single and multiple doses of spironolactone. After the initial dose on day 1, plasma levels of canrenone and 'total metabolites' were higher in the young than in the elderly group, and significant differences were found between the two age groups in the AUC for both canrenone and 'total metabolites' (p < 0.05). However, these differences between the two age groups diminished after multiple dosing on day 8, and the steady state pre-dose plasma levels of canrenone and 'total metabolites' were significantly higher in the elderly subjects. Both canrenone and canrenoic acid were extensively bound to plasma protein, but no differences (p > 0.05) were found between the two age groups in protein binding. Observed differences in plasma levels after single and multiple dosing between young and old subjects may be consequences of many factors such as 1) a proportionate shift in metabolism with age; 2) impaired oral absorption of the parent compound; and/or 3) altered volume of distribution of the drug.
The disposition of acetylsalicylic acid (ASA) and its metabolites (salicylate, salicyluric acid and salicyl glucuronides) was studied in male and female patients of different ages. Plasma levels of ASA and salicylate (SA) were found to be significantly higher in the females (young and elderly), whereas plasma levels of salicyluric acid were found to be significantly higher in the elderly (male and female) groups. The lower renal clearance of salicyluric acid leads to the accumulation of that compound in the aged. The higher plasma levels of ASA in females appeared to be due to an intrinsically lower metabolic activity in that group, while the higher plasma level of SA in the females is suggested to be a consequence of a slower rate of uptake of salicylate to the site of glycine conjugation by the liver, and to a lesser extent by an intrinsically lower metabolic activity.
This thesis concludes that for drugs exclusively eliminated unchanged by the kidney, the change in drug disposition during the ageing process can be predicted from the patients^ degree of renal function, but for drugs extensively metabolised by the liver, there are still no hard rules to predict the effects of ageing on human drug metabolism.