Albert P. Li - Transporters and Drug-Metabolizing Enzymes in Drug Toxicity

While the conventional preclinical and clinical safety evaluation are essential to the assessment of drug safety, additional considerations are needed to avoid the occurrence of idiosyncratic drug toxicity. I have previously proposed that drug safety assessment requires a comprehensive, multidisciplinary approach (8, 9) with input from pharmacologists, toxicologists, epidemiologists, population geneticists, and especially drug metabolism/pharmacokinetics (DMPK) experts to provide insight toward the possible risk factors discussed above.

Key parameters to be considered for drug safety evaluation based on this comprehensive approach include the following: (i) Pharmacology: Possible toxicity due to drug–target interactions, including interactions with unintended molecular targets, or with molecular targets in unintended organs. (ii) Chemistry: Chemical scaffolding and side chains with safety concerns. (iii) Toxicology: Toxicity in animals in vivo , and in relevant animal and human cells in culture. (iv) DMPK: Safety concerns due to toxification or detoxification, organ distribution, clearance, and pharmacokinetic drug–drug interactions. (v) Risk factors: Physiological, environmental, and genetic factors that may enhance a patient's susceptibility. It is proposed that this integrated, multidisciplinary approach to safety evaluation may enhance the accuracy of the prediction of drug safety and thereby the efficiency of drug development (8, 9).

A major doctrine in toxicology is the Paracelsus hypothesis:

All things are poison, and nothing is without poison; only the dose makes a thing not a poison .

When Philippus Aureolus Theophrastus Bombastus von Hohenheim (10, 11) made this statement which has become the cornerstone of the field of toxicology, he meant dose to individuals. An often cited example is that drinking too much water, a universally accepted non‐poison, can lead to fatalities due to a phenomenon known as hyponatremia, lowering of plasma sodium concentrations due to over dilution of plasma, leading to hypo‐osmolality‐related fatal events (12, 13).

Based on the Multiple Determinant Hypothesis, I would like to propose a modernization to the Paracelsus doctrine for drug toxicity:

The dose makes the poison, whilst individuals make the dose .

1 1 Mosedale M, Watkins PB. “Understanding idiosyncratic toxicity: lessons learned from drug‐induced liver injury”. J Med Chem 2020; 63(12): 6436–6461.

2 2 Stepan AF, Walker DP, Bauman J, Price DA, Baillie TA, Kalgutkar AS, et al. “Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States”. Chem Res Toxicol 2011; 24(9): 1345–1410.

3 3 Li AP. “A review of the common properties of drugs with idiosyncratic hepatotoxicity and the ‘multiple determinant hypothesis’ for the manifestation of idiosyncratic drug toxicity”. Chem Biol Interact 2002; 142(1–2): 7–23.

4 4 Collins JM. “Idiosyncratic drug toxicity”. Chem Biol Interact 2002; 142(1–2): 3–6.

5 5 Park BK, Kitteringham NR, Powell H, Pirmohamed M. “Advances in molecular toxicology‐towards understanding idiosyncratic drug toxicity”. Toxicology 2000; 153(1–3): 39–60.

6 6 DiMasi JA, Grabowski HG, Hansen RW. “The cost of drug development”. N Engl J Med 2015; 372(20): 1972.

7 7 Wouters OJ, McKee M, Luyten J. “Estimated research and development investment needed to bring a new medicine to market, 2009–2018”. JAMA 2020; 323(9): 844–853.

8 8 Li AP. “A comprehensive approach for drug safety assessment”. Chem Biol Interact 2004; 150(1): 27–33.

9 9 Li AP. “An integrated, multidisciplinary approach for drug safety assessment”. Drug Discov Today 2004; 9(16): 687–693.

10 10 Mann RD. “Famous names in toxicology. Paracelsus‐‐born 500 years ago”. Adverse Drug React Toxicol Rev 1993; 12(2): 81–82.

11 11 Wilks MF. “Bringing chemistry to medicine‐the contribution of Paracelsus to modern toxicology”. Chimia (Aarau) 2020; 74(6): 507–508.

12 12 Oh RC, Malave B, Chaltry JD. “Collapse in the heat‐from overhydration to the emergency room‐three cases of exercise‐associated hyponatremia associated with exertional heat illness”. Mil Med 2018; 183(3–4): e225–e228.

13 13 O'Brien KK, Montain SJ, Corr WP, Sawka MN, Knapik JJ, Craig SC. “Hyponatremia associated with overhydration in U.S. Army trainees”. Mil Med 2001; 166(5): 405–410.

Minjun Chen, Kristin Ashby, and Yue Wu

Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA

Drug‐induced liver injury (DILI) can lead to serious clinical outcomes, including acute liver failure. Current research on DILI suggests that it is mostly idiosyncratic. It is a significant concern for drug developers and agencies, and the current testing strategies provide an unacceptably high number of false negatives [1]. In past decades over 50 approved drugs have either been withdrawn from the market or have become the focus of regulatory actions, including the addition of boxed warnings and other product labeling modifications due to DILI [2, 3]. Hepatotoxicity also is cited as one of the leading reasons for drug development failure, accounting for over 20% of failed clinical trials due to drug safety issues [4]. In 2009, the US FDA published guidance on the clinical evaluation of DILI before premarketing approval, which aimed to address the collection and evaluation of laboratory measurements that signal the potential for DILI during clinical trials [5].

The liver is the major organ for drug metabolism and receives over 80% of its blood flow from the gastrointestinal tract. It contains several enzymes with biotransformation capacity for a large variety of foreign compounds, including therapeutic medications ( Figure 2.1). P450 enzymes in phase I metabolism catalyze lipophilic drug molecules into water‐soluble metabolites in order to eliminate them from the body. However, the biotransformation of these drug molecules can also form toxic reactive metabolites (RMs), which covalently bind and modify biological macromolecules such as enzymes, proteins and DNA, affecting their functions and potentially leading to toxicity. The physiological role of phase II reactions is to form conjugated products that are more water soluble than the original xenobiotic or active phase I metabolites; nevertheless, it also generates reactive conjugations that could result in toxicity.

Figure 2.1 The physiological process of drug metabolism and transport and the role of enzymes in formation of reactive metabolites and accumulation of toxic bile acids, two proven mechanisms leading to drug‐induced liver injury.

The inhibition of hepatic transporters such as the bile salt export pump (BSEP) presumably could cause toxic bile acids to accumulate in the liver and also is considered an important mechanism leading to DILI. In this chapter we will focus on drug metabolism and hepatic transporters, and their relationships to DILI. We will briefly introduce the enzymes involved in phase I and phase II hepatic metabolism and their roles in forming chemically RMs. Next, we will review the role of RMs in toxicity and how to detect and measure them using in silico and experimental approaches, as well as strategies for mitigating the risk of RMs in the drug discovery phase. We will also discuss the role of hepatic transporters and their relationship to hepatotoxicity. Finally, we will summarize the genetic variants of drug metabolism enzymes and hepatic transporters and their impact on pharmacokinetic behavior and drug safety.