Clinical pharmacological aspects of drug toxicity testing

Drugs are xenobiotics. Absorption, distribution, and elimination depend on their physico-chemical character. Lipophilic drugs are usually inactivated or activated by biotransformation systems. Nearly all metabolic pathways are influenced by drugs. Damage of the DNA includes the possible risk of mutation and inducton of cancer. Severe side-effects of drugs and some drug disasters in the past promoted physicians and legislators to elaborate new guidelines for the safety of drugs for human beings. The different requirements of the guidelines are compared using oral contraceptives as example. The problem in studies of drug metabolism in drug safety evaluation is to find out a species in which drug disposition is nearly identical to that in man, because the rat and the mouse are poor predictors of the human situation. In the future, extensive studies on comparative drug metabolism need to be done. The increasing number of hepatic adenomas and neoplasmas in the past ten years in women taking oral contraceptives initiated studies on metabolism of estrogens. Hydroxylation of ethinylestradiol at C 2 has been shown to be the key to understand the activation to arene oxides which bind covalently to nucleic acids and proteins. This metabolic pathway may explain the potential toxicity and cancerogenicity. This example should stress that drug metabolism is part of drug safety evaluation.