Covalent Binding and Tissue Distribution/Retention Assessment of Drugs Associated with Idiosyncratic Drug Toxicity

Takakusa, Hideo; Masumoto, Hiroshi; Yukinaga, Hideo; Makino, Chie; Nakayama, S.; Okazaki, Osamu; Sudo, Kenichi

doi:10.1124/dmd.108.021725

Cited by 80 publications

(74 citation statements)

References 27 publications

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“…Zia-Amirhosseini et al (1994) proposed that covalent binding of tolmetin to human proteins was through an acyl glucuronide, which reacted with proteins either via a nucleophilic displacement or a Schiff base intermediate. Acyl glucuronide-mediated covalent binding has also been reported for valproic acid and zomepirac (Takakusa et al, 2008). In this study, alkaline digestion of human plasma protein pellets released eltrombopag in addition to M1 (Fig.…”

Section: Discussionmentioning

confidence: 92%

Metabolism and Disposition of Eltrombopag, an Oral, Nonpeptide Thrombopoietin Receptor Agonist, in Healthy Human Subjects

Deng¹,

Madatian²,

Wire³

et al. 2011

Drug Metab Dispos

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ABSTRACT:The metabolism and disposition of eltrombopag, the first-in-class small molecule human thrombopoietin receptor agonist, were studied in six healthy men after a single oral administration of a solution dose of [ 14 C]eltrombopag (75 mg, 100 Ci). Eltrombopag was well tolerated. The drug was quickly absorbed and was the predominant circulating component in plasma (accounting for 63% of the total plasma radioactivity). A mono-oxygenation metabolite (M1) and acyl glucuronides (M2) of eltrombopag were minor circulating components. The predominant route of elimination of radioactivity was fecal (58.9%). Feces contained approximately 20% of dose as glutathione-related conjugates (M5, M6, and M7) and another 20% as unchanged eltrombopag. The glutathione conjugates were probably detoxification products of a p-imine methide intermediate formed by metabolism of M1, which arises through cytochrome P450-dependent processes. Low levels of covalently bound drug-related intermediates to plasma proteins, which could result from the reaction of the imine methide or acyl glucuronide conjugates with proteins, were detected. The bound material contributes to the longer plasma elimination half-life of radioactivity. Renal elimination of conjugates of hydrazine cleavage metabolites (mostly as M3 and M4) accounted for 31% of the radiodose, with no unchanged eltrombopag detected in urine.

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Section: Discussionmentioning

confidence: 92%

Metabolism and Disposition of Eltrombopag, an Oral, Nonpeptide Thrombopoietin Receptor Agonist, in Healthy Human Subjects

Deng¹,

Madatian²,

Wire³

et al. 2011

Drug Metab Dispos

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“…The skin toxicity and allergic reactions observed with nevirapine are rather ascribed to its metabolite, 12-hydroxynevirapine (62), which can be further transformed into a QM (63). However, the relationship between a QM derived from nevirapine and these side effects is just hypothesized [80].…”

Section: An Update About Qms and Cancermentioning

confidence: 99%

“…A QM (63) that is derived from the hydroxymethyl metabolite of NEV had been identified previously [62]. Although it is not the only electrophilic compound generated, it could participate in the generation of the NEV adducts that were detected in the liver tissue of treated patients [63].…”

Section: Examples Of Chemically-derived Qmsmentioning

confidence: 99%

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

Dufrasne¹,

Gelbcke²,

Nève³

et al. 2011

CMC

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Abstract:The importance of reactive drug metabolites in the pathogenesis of drug-induced toxicity has been investigated since the early 1950s, mainly to reveal the link between toxic metabolites and chemical carcinogenesis. This review mainly focuses on biologically active compounds, which generate reactive quinone methide (QM) intermediates either directly or after bioactivation. Several examples of anticancer drugs acting through the generation of QM electrophiles are given. The use of those drugs for chemotherapeutic purposes is also discussed. The key feature of those QM-generating drugs is their reactivity toward specific nucleophilic biological targets. Modulation of their reactivity represents a challenge for medicinal chemists because, depending on the reactivity of these QM intermediates, their interaction with critical proteins can alter the function of these key proteins and induce a wide variety of responses with functional consequences. Among the possible consequences, antiproliferative effects could be exploited for chemotherapeutic purposes. Information on how such QM-generating drugs can affect individual target proteins and their functional consequences are required to help the medicinal chemist in the design of more specific QM-generating molecules for chemotherapeutic use.

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“…Earlier investigations of whether CB can estimate DILI were performed with positive drugs (Evans et al, 2004;Masubuchi et al, 2007;Takakusa et al, 2008), but only a few researchers have made comparisons with examples of safe drugs. However, it was recently reported that the total daily dose of drugs improves the discrimination between hepatotoxic and nontoxic drugs based on in vitro CB intrinsic clearance (Obach et al, 2008;Bauman et al, 2009).…”

Section: Evaluation Of Drug-induced Liver Injury By Covalent Bindingmentioning

confidence: 99%

Evaluation of the Potential for Drug-Induced Liver Injury Based on in Vitro Covalent Binding to Human Liver Proteins

Usui¹,

Mise²,

Hashizume³

et al. 2009

Drug Metab Dispos

141

123

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ABSTRACT:Prediction of idiosyncratic drug-induced liver injury (DILI) is difficult, and the underlying mechanisms are not fully understood. However, many drugs causing DILI are considered to form reactive metabolites and covalently bind to cellular macromolecules in the liver. The objective of this study was to clarify whether the risk of idiosyncratic DILI can be estimated by comparing in vitro covalent binding (CB) levels among 12 positive compounds (acetaminophen, alpidem, bromfenac, carbamazepine, diclofenac, flutamide, imipramine, nefazodone, tacrine, ticlopidine, tienilic acid, and troglitazone) for DILI and 12 negative compounds (acetylsalicylic acid, caffeine, dexamethasone, losartan, ibuprofen, paroxetine, pioglitazone, rosiglitazone, sertraline, theophylline, venlafaxine, and zolpidem). After incubation with human liver microsomes in the presence of NADPH, there was a large overlap in the distribution of CB amounts between the positive and negative groups. On addition of UDP-glucuronic acid (UDPGA) as a cofactor for glucuronidation, the CB levels of bromfenac and diclofenac were increased. With addition of nucleophilic glutathione (GSH), values for most compounds were decreased. However, separation of the two groups on the basis of CB could not be improved by UDPGA or GSH. Furthermore, CB with human hepatocytes also failed to discriminate positive from negative compounds. Therefore, the CB amount alone is not sufficient for risk assessment of DILI. In contrast, when the CB amount was multiplied by the maximum daily dose, which may reflect maximum hepatic exposure, the two groups did become discriminated. Taken together, our findings suggest that the combination of CB amount and daily dose can estimate the risk of idiosyncratic DILI.

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Covalent Binding and Tissue Distribution/Retention Assessment of Drugs Associated with Idiosyncratic Drug Toxicity

Cited by 80 publications

References 27 publications

Metabolism and Disposition of Eltrombopag, an Oral, Nonpeptide Thrombopoietin Receptor Agonist, in Healthy Human Subjects

Metabolism and Disposition of Eltrombopag, an Oral, Nonpeptide Thrombopoietin Receptor Agonist, in Healthy Human Subjects

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

Evaluation of the Potential for Drug-Induced Liver Injury Based on in Vitro Covalent Binding to Human Liver Proteins

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