DECEMBER 2006 VOLUME 19, NUMBER 12 © Copyright 2006 by the American Chemical Society
Forum PerspectiVes Safety Assessment of Stable Drug Metabolites F. Peter Guengerich Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt UniVersity School of Medicine, NashVille, Tennessee 37232-0146 ReceiVed September 1, 2006
One of the current issues in drug metabolism is regulatory guidelines for metabolites that selectively accumulate in humans. The concern is that some of these drug metabolites could have inherent toxicity and, because they would not be generated at appreciable levels in experimental animals, not show toxicity that could occur upon administration to humans. Some issues are the fraction of metabolism necessary to be concerned, whether a fractional or total mass basis should be used, the usefulness of new regulations in avoiding human problems, and the cost in resources. A Forum expressing views on the title topic from regulatory and industrial scientists follows in this issue of the journal. There are three perspectives (1-3) presenting issues from the viewpoints of select authors from the Food and Drug Administration (FDA) and the pharmaceutical industry. The general issue is the prediction of drug safety and toxicity in humans. Today, there is a widespread appreciation of the role of drug metabolism in safety assessment and in interspecies differences in metabolism (4, 5). Even if the same metabolites are produced in humans and experimental animal species, the level of a particular metabolite may vary considerably between humans and animals (and among individual humans, although that is a separate issue). Sometimes, a particular metabolite is found at a much higher level in humans than in the animal models being used to predict toxicity. This scenario poses a dilemma in that even after the treatment of test animals with high doses of the parent drug, the level of a metabolite in the animals may not approach (or generate a sufficient multiple of) * To whom correspondence should be addressed. Tel: 615-322-2261. Fax: 615-322-3141. E-mail:
[email protected] the amount found in humans. In principle, such a metabolite could be toxic, and the animal tests would not predict potential human toxicity. The issue is not new, and both the pharmaceutical industry and FDA have made proposals (6-8). However, these have been differences of opinion on what the guidelines should encompass, for example, differences in what percentage appearing as a metabolite in humans, compared with animals, constitutes a unique human metabolite for consideration. Should this be 25% (6), 10% (8), or some other percentage? Another point of view is that considerations of percentages is not particularly relevant, and the mass of a metabolite is a better basis (9). The first perspective, by Davis-Bruno and Atrakchi (1), provides an introduction to the issue and discusses the rationale for testing. Two examples are provided, one in which the data led to more tests and one in which no additional studies were recommended. Humphreys and Unger (2) discuss the issue of reactive versus stable products. They also present some cases of possible nontarget activities of stable metabolites, concluding that these have receptors (relevant to toxicity) closely related to the (therapeutic) target receptor. The authors conclude that off-target and unpredicted effects of drug metabolites are rare and discuss reasons why. Finally, they discuss the matter of allocation of time and financial resources to the questions. Smith and Obach (3) propose that the actual abundance (mass) of a unique metabolite is more of an issue than a percentage. Another point of discussion is that when metabolites are administered to animals, they may not reach the sites where they were generated. The authors present a list of 24 drugs that have been withdrawn from the market and address the question
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of whether studies on unique human metabolites would have prevented approvals. This latter analysis is also helpful in sorting recalled drugs into categories of types of toxicity (5, 10). In the past year, I have personally been involved in this area and have several views of my own, which will not be presented here. The points raised in this Forum are good. One of the issues I do feel is important is the demarcation of reactive and stable compounds, which have different mechanisms. The real issue in all of this is predicting drug toxicity in humans from animal studies. Will new guidelines in this area help? Much of the newer in Vitro work in the field is helping us make better predictions about toxicity in pre-clinical animal species, but how are we doing in predicting human toxicity? That is a larger issue, and James Macdonald and I are preparing a review article on some of these issues, which should appear soon in another issue of Chemical Research in Toxicology. The current perspective on the safety assessment of drug metabolites is designed to do two things. First, we would like to bring the issues to the attention of readers (e.g., academic), who may not be aware of the issues, which have been focused largely on the regulatory/industrial arena. Second, we hope to stimulate more thought and discussion in this area, to the end that the best answers will develop on the basis of science.
References (1) Davis-Bruno, K. L., and Atrakchi, A. (2006) A regulatory perspective on issues and approaches in characterizing human metabolites. Chem. Res. Toxicol. 19, 1561-1563.
Guengerich (2) Humphreys, W. G., and Unger, S. E. (2006) Safety assessment of drug metabolites: characterization of chemically stable metabolites. Chem. Res. Toxicol. 19, 1564-1569. (3) Smith, D. A., and Obach, R. S. (2006) Metabolites and safety: what are the concerns and how should we address them? Chem. Res. Toxicol. 19, 1570-1579. (4) Evans, D. C., Watt, A. P., Nicoll-Griffith, D. A., and Baillie, T. A. (2004) Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem. Res. Toxicol. 17, 3-16. (5) Liebler, D. C., and Guengerich, F. P. (2005) Elucidating mechanisms of drug-induced toxicity. Nat. ReV. Drug DiscoVery 4, 410-420. (6) Baillie, T. A., Cayen, M. N., Fouda, H., Gerson, R. J., Green, J. D., Grossman, S. J., Klunk, L. J., LeBlanc, B., Perkins, D. G., and Shipley, L. A. (2002) Drug metabolites in safety testing. Toxicol. Appl. Pharmacol. 182, 188-196. (7) Hastings, K. L., El-Hage, J., Jacobs, A., Leighton, J., Morse, D., and Osterberg, R. E. (2003) Drug metabolites in safety testing. Toxicol. Appl. Pharmacol. 190, 91-92 (plus author reply 93-94). (8) Food and Drug Administration. (2005) Guidance for Industry. Safety Testing of Drug Metabolites, pp 1-11. (9) Smith, D. A., and Obach, R. S. (2005) Seeing through the mist: abundance versus percentage. Commentary on metabolites in safety testing. Drug Metab. Dispos. 33, 1409-1417. (10) Walgren, J. L., Mitchell, M. D., and Thompson, D. C. (2005) Role of metabolism in drug-induced idiosyncratic hepatotoxicity. Crit. ReV. Toxicol. 35, 325-361.
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