or delay the onset of common but deadly disorders. The explosion in knowledge of the human genome has been instrumental in the development of novel therapeutic targets in the past decade, allowing the development of small molecules, biologics, and gene therapy to retard or completely abolish the progression of diseases via the modulation of key pathways. Human life span has been extended in most developed countries due to enhancements in health care approaches.
Unexpected human‐specific drug toxicity has been, and continues to be a major challenge in drug development (1–5). Pharmaceuticals by nature are biologically active chemicals designed to interact with biological pathways. Key uncertainties are the unintended biological effects which may lead to damage. Unintended drug toxicity is one of the major reasons for clinical trial failures as well as withdrawal or greatly limited use of drugs that have received regulatory approval. Unintended and unexpected drug toxicities are responsible for the high costs and time required for drug development. The most recent estimation of the cost for development of a new drug is over $1 billion USD, with the average time span from discovery to market of over 10 years (6, 7).
In drug development, approaches to develop drugs with acceptable safety margin to patients involve extensive preclinical evaluation in multiple species of laboratory animals. Only after the preclinical data support the safety of a drug candidate can it be submitted for approval by regulatory agencies for phase 1, 2, and 3 clinical trials. A drug is approved for marketing after the clinical trials support its safety and efficacy. The occurrence of unexpected toxicity for drug candidates with acceptable safety profile from preclinical safety studies is one of the major reasons for clinical trial failure, illustrating that nonhuman animals may not provide adequate information for the assessment of human drug toxicity. However, numerous drugs approved for marketing based on clinical trial demonstration of safety have been withdrawn from the market or have been restricted in use due to unacceptable adverse events leading to deaths. The occurrence of unacceptable drug toxicity after a drug is marketed to the human population illustrates that clinical trials do not have the statistical power to assure safety when millions of patients are exposed to a new drug. The paradigm for drug safety evaluation of preclinical safety in laboratory animals followed by regulatory human clinical trials therefore is not always adequate.
I strongly advocate the transition of the practice of toxicology from an empirical to a mechanistic discipline. A thorough mechanistic understanding of the onset of the toxic events is necessary for the identification of risk factors and the estimation of the probability of the patient population with the risk factors based on genetic polymorphism, coadministered prescribed and non‐prescribed medications, disease status, and life style factors such as diet, substance abuse, alcohol consumption, and the use of unregulated diet supplements and herbal medicines.
1.2 Fate of an Orally Administered Drug
The following are the events likely to occur with an orally administered drug.
Enteric events: An orally administered drug undergoes the following events:
1 Metabolism by intestinal microflora.
2 Entry into enterocytes via diffusion or transporter‐mediated uptake.
3 Metabolism by drug‐metabolizing enzymes in the enterocytes.
4 Efflux to the intestinal lumen via efflux transporters.
5 Entry of the drug and its metabolites into the portal circulation.
Hepatic events: Upon entry of a drug and its enteric metabolites into the portal circulation, the following events occur:
1 Entry into hepatocytes via diffusion or transporter‐mediated uptake.
2 Metabolism by drug‐metabolizing enzymes in the hepatocytes.
3 Excretion of parent drug and/or metabolites to the intestine as bile via diffusion or efflux transporters followed by excretion into the feces or reentry into the portal circulation (enterohepatic recirculation) via diffusion or uptake transporters.
4 Entry into the systemic circulation.
Extrahepatic events: Upon entry of a drug and its hepatic metabolites into the systemic circulation, the following events occur:
1 Entry into extrahepatic target cells via diffusion or transporter‐mediated uptake.
2 Metabolism by drug‐metabolizing enzymes in the target cells.
3 Exit of parent drug and/or metabolites from the target cells to the systemic circulation.
4 Excretion via urinary, perspiratory, respiratory pathways.
The manifestation of toxicity of the drug in question, either due to the parent molecule or its metabolites, is dependent on the concentration of the toxic moiety at the ultimate target. Metabolism (metabolic clearance, activation, and detoxification), uptake transport, and efflux transport can play critical roles on whether the toxic moiety will reach the critical concentration leading to the onset of toxicity.
1.3 The Multiple Determinant Hypothesis for Idiosyncratic Drug Toxicity
A perplexing observation in drug toxicity is the phenomenon of idiosyncratic drug toxicity which occurs at an incidence of less than 1 per 5000 patient‐years, thereby cannot be detected with conventional regulatory clinical trials but would be clearly identified after marketing of a drug with a large patient population being exposed (1–5). To explain this phenomenon and to provide a possible mitigating strategy, I have proposed the multiple determinant hypothesis (3) which states that idiosyncratic drug toxicity occurs due to a confluence of multiple discrete events in the individual succumbing to drug toxicity (Figure 1.1).
Figure 1.1 Schematic illustration of the Multiple Determinant Hypothesis of Idiosyncratic Drug Toxicity. Each circle represents a key determinant due to genetic and/or environmental factors. The hypothetical situation shown here is the confluence of the five determinants leading to severe liver toxicity in a patient at the time of drug administration: 1. Increased transporter‐mediated uptake, leading to increased liver drug concentration. 2. Increased metabolic activation due to the co‐exposure to enzyme inducers, leading to higher rate of formation of toxic/reactive metabolites. 3. Compromises metabolic detoxification due to co‐exposure to GSH depleting agents and/or inhibitors of phase 2 conjugating pathways. 4. Sensitized inflammatory response due to diseases or exposure to sensitizing agents. 5. Compromised efflux of bile salt due to genetic polymorphism of BSEP or co‐exposure to BSEP inhibitors.
I would like to illustrate the role of drug transport and metabolism in the manifestation of idiosyncratic drug toxicity based on the Multiple Determinant Hypothesis.
This hypothetical drug, T, is a substrate of an uptake transporter. Upon uptake into the hepatocytes, T is metabolized to a reactive metabolite, T*. T* is the ultimate toxicant which reacts with key cellular proteins, leading to cell death. T* also can form protein conjugates, leading to the formation of a neoantigen which would elicit a cytotoxic inflammatory event, leading to liver failure. However, T also undergoes metabolic clearance via glucuronidation and sulfation, with the conjugates excreted via transporter‐mediated efflux. T* can be detoxified via glutathione S‐transferase
