Drug-Induced Agranulocytosis

Heimpel, Hermann

doi:10.1007/bf03259896

Cited by 41 publications

(11 citation statements)

References 97 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Aminopyrine, a drug for the control of postoperative pain, was one of the first drugs to be associated with high incidence of agranulocytosis [129,130] and thus was withdrawn from the market. Aminopyrine breath test has been widely used to assess liver metabolic function [131][132][133][134].…”

Section: Aminopyrinementioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

149

View full text Add to dashboard Cite

Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

show abstract

Section: Aminopyrinementioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

149

View full text Add to dashboard Cite

show abstract

“…First, the metabolites could simply be toxic to neutrophils, bone marrow cells (i.e., cells of the granulocytic lineage), and/or the stromal cells which support the growth and maturation of the granulocytic cells (Fig. 2) (Heimpel 1988;Smith et ai, 1988;Uetrecht, 1988Uetrecht, , 1989Uetrecht, , 1990. 1,4-Benzoquinone, a metabolite of benzene, and shown in this in vitro study to be a metabolite of CGS 12094, has been shown to interfere with granulopoiesis in bone marrow cultures through a cytotoxic mechanism directed against the granulocytic cells themselves and/or stromal cells (Smith et at, 1988).…”

Section: Discussionmentioning

confidence: 99%

“…1,4-Benzoquinone, a metabolite of benzene, and shown in this in vitro study to be a metabolite of CGS 12094, has been shown to interfere with granulopoiesis in bone marrow cultures through a cytotoxic mechanism directed against the granulocytic cells themselves and/or stromal cells (Smith et at, 1988). However, a cytotoxic event would not be expected to produce a low incidence (<0.3%) of agranulocytosis as seen with prinomide administration or be idiosyncratic in nature (Heimpel, 1988;Uetrecht, 1989b).…”

Section: Discussionmentioning

confidence: 99%

“…A second possible mechanism for the generation of agranulocytosis is an immune-mediated mechanism (Heimpel, 1988, Uetrecht, 1989aHofstra et al, 1992). Reactive metabolite, generated during the MPO-mediated metabolism of a drug, by binding to a cellular macromolecule of the neutrophil, could act as a hapten or immunogen and result in the production of antibodies and the possible rapid destruction of circulating cells and bone marrow cells that express an antigenic determinant similar to the hapten (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…2). While the destruction of bone marrow cells by antibodies is a possibility, many patients with agranulocytosis in which "antidrug" antibodies have been detected, exhibit bone marrow conditions characterized by hypercellularity of the granulopoietic lineage and maturation arrest suggesting that only peripheral destruction of neutrophils is occurring (Heimpel, 1988). Even though 1,4-benzoquinone has been shown to be a myelotoxic compound, the production of 1,4-benzoquinone and/or other CGS 12094 metabolites in the neutrophil and subsequent binding to cellular macromolecules, thus forming a hapten, would suggest that an immune-mediated mechanism for prinomide-induced idiosyncratic agranulocytosis is possible as well (Fig.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Activation of CGS 12094 (Prinomide Metabolite) to 1,4-Benzoquinone by Myeloperoxidase: Implications for Human Idiosyncratic Agranulocytosis

Parrish¹,

Schlosser²,

Kapeghian³

et al. 1997

Toxicol Sci

View full text Add to dashboard Cite

Many marketed Pharmaceuticals are known to cause idiosyncratic agranulocytosis in humans. Similarly prinomide, an antiinflammatory drug, was associated with a low incidence of agranulocytosis (<0.3%) in clinical trials, even though chronic toxicity studies in rodents and primates showed no evidence of agranulocytosis with either prinomide or its parahydroxy metabolite, CGS 12094. To investigate mechanisms for this human specific toxicity, experiments were conducted to study the metabolism of prinomide and CGS 12094 by myeloperoxidase (MPO), a major enzyme of neutrophils and leukocyte progenitor cells. Although prinomide was not metabolized by human MPO, CGS 12094 was rapidly metabolized (>90%; 2 min); this reaction was dependent on H 2 O 2 and MPO and was inhibited by azide. During the MPO-catalyzed metabolism of CGS 12094, reactive intermediates that irreversibly bound to protein and cysteine were generated. One of the reactive metabolites generated was identified by mass spectroscopy and trapping with cysteine as 1,4-benzoquinone, a compound implicated in the myelotoxicity associated with benzene. Thus during conditions which lead to elevated levels of H 2 O 2 (e.g., active inflammation), CGS 12094 is rapidly metabolized by MPO to reactive intermediates that may be related to prinomide-induced O 1997 Soetely of Toxicology.

show abstract