Physiological factors affecting drug toxicity.

Physiological factors that affect the fate of drugs in the body and thereby have effects on their pharmacology and toxicology involve the systems that control absorption, distribution, metabolism, and excretion. The main factors are disease, genetics, and age. Nutritional status, sex, hormonal status (e.g., the effects of pregnancy), and circadian rhythm have important influences. Maternal toxicity will affect the fetus. The absorption and excretion of drugs are frequently reduced by diseases. Excretion is reduced by impaired renal function, often found in the elderly, which may increase the toxic response. Distribution is affected by body weight and build, for example, the proportion of fat. The disposition of many drugs has been shown to be significantly influenced by circadian rhythms such that therapeutic doses may exhibit toxicity if administered at an inappropriate time of day. Metabolism is modified by environmental influences including previous food and drug experience, and various factors such as age, sex, and disease. Intersubject variations in drug disposition can be very great with possibly severe consequences for the individual; in this regard, knowledge of genetic polymorphism in drug metabolizing enzymes is rapidly increasing. The toxicology of a drug may be profoundly affected by a particular disease state, for example, the administration of a drug that might be a tumor promoter when a cancerous or precancerous condition exists. These effects are illustrated with examples from the literature and recent studies undertaken in the Bureau of Drug Research.