BIOACTIVATION AND BIOINACTIVATION OF DRUGS AND DRUG METABOLITES - RELEVANCE TO ADVERSE DRUG-REACTIONS

Adverse drug reactions that cannot be predicted from the pharmacologic al properties of the drug and which are not easily reproduced in labor atory animals are a major complication of drug therapy. It is necessar y to investigate the mechanisms of such reactions in order to (1) defi ne structural features within a given drug molecule which are responsi ble for causing toxicity and (2) to identify those individuals who are particularly sensitive to a given drug reaction. In theory, drug toxi city may arise by direct toxicity, genotoxicity or immune-mediated tox icity caused by either parent drug or chemical. In this respect chemic ally reactive metabolites are of particular importance and the balance between bioactivation and bioinactivation pathways of drug metabolism will be a critical factor in both the type and extent of toxicity. We have therefore developed in vitro techniques that incorporate human c ells for the detection and characterization of stable, chemically reac tive and cytotoxic metabolites. In such experiments bioactivation (by CYP1A, CYP2D6, CYP3A, etc.) can be investigated by use of a liver bank , while lymphocytes provide accessible human cells, which can be obtai ned from both patients and volunteers, genotyped and/or phenotyped for particular drug-metabolizing enzymes (eg. glutathione transferase mu) . The relevance of in vitro experiments to drug toxicity observed in h umans will be illustrated by reference to studies with anticonvulsants and antimalarials.