Drug metabolism under pathological and abnormal physiological states in animals and man.

The activity of microsomal drug-metabolizing enzymes is altered by several pathological or abnormal physiological states, such as changes in nutritional status, liver, heart or kidney diseases, hormonal disturbances, pregnancy, tumour-bearing state, adjuvant arthritis, changes in reticuloendothelial system and environmental factors (stress, irradiation, heavy metals). The activities of other metabolic pathways, such as glucuronidation, sulphate conjugation, acetylation and alcohol oxidation are generally affected to lesser extents. Rats are most commonly used in drug metabolism studies, and it is important to know that the activity of most of the microsomal drug-metabolizing enzymes is higher in males than in females through androgen action which is readily impaire drug-metabolizing enzymes in male rats are thus manifested by two mechanisms; one is by impairment of androgen action and the other is by depression of the basic enzymic activity. Therefore, those effects of pathological states, observed only in male rats but not in females, are generally not seen in other species of animals, including man. The effects of starvation, hyperthyroidism, adrenal insufficiency, diabetes and morphine administration are cases where changes in metabolism are due solely to impairment of androgen action. In other pathological cases, those drug-metabolizing enzymes showing sex differences are depressed more markedly in male rats than those showing no clear sex difference. The author therefore recommends the use of female rats in the evaluation of the effects of pathological states on hepatic microsomal drug-metabolizing enzymes. Generally, changes in activity of the hepatic enzymes reflect closely the changes in the rates of drug metabolism in vivo. However, the protein-binding of drugs, hepatic blood flow and renal function are also known to affect the rate of drug metabolism and excretion in vivo, and therefore changes of these factors in pathological states should also be taken into consideration.