A review of the common properties of drugs with idiosyncratic hepatotoxicity and the "multiple determinant hypothesis" for the manifestation of idiosyncratic drug toxicity

Abstract

Idiosyncratic drug toxicity is generally believed to be a phenomenon that cannot be readily evaluated experimentally. Reasons for this difficulty include the following: 1. It is a rare event (<1/5,000) and therefore impossible to be studied in clinical trials; 2. It is a human-specific event not detectable in experimental animals. To aid the understanding of idiosyncratic toxicity and to develop an experimental strategy for this phenomenon, a hypothesis is proposed. The hypothesis states that the low frequency of idiosyncratic drug toxicity is due to the requirements for the occurrence of multiple critical and discrete events, with the probability for the occurrence of idiosyncratic drug toxicity as a product of the probabilities of each event. The key determinants of these critical events are proposed to be: 1. Chemical properties; 2. exposure; 3. environmental factors; and 4. genetic factors. Based on this hypothesis, idiosyncratic drug toxicity can be evaluated experimentally via studying these key determinants. The chemical properties critical to idiosyncratic drug toxicity are identified via a review of the common properties of drugs that cause idiosyncratic liver toxicity. These properties include: 1. Formation of reactive metabolites. 2. Metabolism by P450 isoforms. 3. Preponderance of P450 inducers, and 4. Occurrence of clinically significant pharmacokinetic interactions with co-administered drugs. Based on this review, it is proposed that these common properties may be useful experimental endpoints for the prediction and therefore avoidance of the selection of drug candidates with idiosyncratic drug toxicity for further development.