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Introduction: Idiosyncratic drug reactions (IDRs) that involve the formation of toxic metabolites followed by covalent binding to cellular proteins often go undiscovered until after post-marketing. The goal of this article is to review the current status of IDRs, potential mechanisms and the challenges associated with predicting drug toxicity. Areas covered: The authors review the metabolic pathways of five select classes of sulfur-containing drugs (captopril, troglitazone, tienilic acid, zileuton, methimazole and sudoxicam) suggesting that bioactivation plays a crucial role in the occurrence of IDRs. The reader will gain further awareness that the sulfur atom can propagate as the bioactivation site for the formation of reactive and conceivably toxic metabolites. As such, it is the body's capacity to detoxify these drug products that may determine whether IDRs occur. Expert opinion: Incomplete understanding of mechanisms culminating in IDR occurrence represents a monumental impediment toward their abrogation. Moreover, current technology utilized to predict their manifestation (including structure-toxicity relationships) is not infallible and thus, development of novel tools and strategies is indispensible. In an attempt to streamline clinical development and drug approval processes, consortiums have been instated under the US FDA Critical Path Initiative. Collectively, these parameters along with the availability of validated biomarkers and new/updated regulatory guidance could positively influence the outcome of drug toxicity profiles and direct future drug development.
Department of Clinical Pharmacology, Global Drug Development, Allergan, Inc. , Irvine, CA 92612-1599 , USA.
This article was published in the following journal.
Name: Expert opinion on drug metabolism & toxicology
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Enzymes that catalyze the transposition of a sulfur-sulfur bond. EC 5.3.4.
Enzymes that catalyze the transfer of sulfur atoms (2.8.1), sulfur groups (2.8.2) or coenzyme A (2.8.3). EC 2.8.
Stable sulfur atoms that have the same atomic number as the element sulfur, but differ in atomic weight. S-33, 34, and 36 are stable sulfur isotopes.
Unstable isotopes of sulfur that decay or disintegrate spontaneously emitting radiation. S 29-31, 35, 37, and 38 are radioactive sulfur isotopes.
The metabolism of drugs and their mechanisms of action.
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