Protein Covalent Binding of Maxipost Through a Cytochrome P450-Mediated Ortho-Quinone Methide Intermediate in Rats

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.

Section: Discussionmentioning

confidence: 99%

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

Deng¹,

Madatian²,

Wire³

et al. 2011

“…They proposed that the mechanism of adduct formation would be via Michael addition between an -amine of lysine and an ortho-quinone methide, a reactive intermediate formed as a result of CYP3A activation of BMS-204352 (Zhang et al, 2003). Hence, we propose that to favor the Michael addition between HKI-272 and the lysine reside of HSA, the electrophilicity of ␣,␤-unsaturated amide of HKI-272 needs to be enhanced.…”

Section: Downloaded Frommentioning

confidence: 99%

Characterization of HKI-272 Covalent Binding to Human Serum Albumin

Wang¹,

Li-Chan²,

Atherton³

et al. 2010

“…14 C]BMS-204352 (5 Ci/mg, radiochemical purity 99.5%), des-fluoro BMS-204352 lysine adduct (BMS-349821, 98% pure), and [ 13 CD 3 ]BMS-204352 (internal standard for LC/MS/MS analysis) were synthesized at Bristol-Myers Squibb (Dischino et al, 2003;Zhang et al, 2003).…”

Section: Chemicals [mentioning

confidence: 99%

Metabolism, Pharmacokinetics, and Protein Covalent Binding of Radiolabeled Maxipost (Bms-204352) in Humans

Zhang¹,

Krishna²,

Wang³

et al. 2004

Self Cite

MaxiPost [(3S)-(؉)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one); BMS-204352] is an investigational maxi-K channel opener to treat ischemic stroke. This study reports the disposition, metabolism, pharmacokinetics, and protein covalent binding of 14 C-labeled MaxiPost in healthy male volunteers as well as in dogs and rats. After each human subject received a single dose of 10 mg 14 C-labeled BMS-204352 (50 Ci) as a 5-ml intravenous infusion lasting 5 min, the plasma radioactivity concentrations showed a unique profile, wherein the concentration appeared to increase initially, followed by a terminal decline. The mean terminal t 1/2 of plasma radioactivity (259 h) was prolonged compared with that of unchanged parent (37 h). Furthermore, the extractability of radioactivity in plasma decreased over time, reaching approximately 20% at 4 h after dosing. The unextractable radioactivity was covalently bound to plasma proteins through a des-fluoro-des-methyl BMS-204352 lysine adduct. Unchanged BMS-204352 and minor metabolites were identified in plasma extract following protein precipitation. The recovery of the radioactive dose in urine and feces was nearly complete in 14-day collections (approximately 37% in urine and 60% in feces). The N-glucuronide of the parent was the prominent metabolite in urine (16.5% of dose), whereas the parent was a major drug-related component in feces (11% of dose). Similar disposition, metabolism, pharmacokinetic, and protein covalent binding properties of 14 C-labeled BMS-204352 were observed in humans, dogs, and rats.Stroke is a major cause of death and long-term disability, affecting more than 700,000 people in the United States annually (Williams et al., 1999). Acute ischemic stroke is the most common form, producing pathologically fatal levels of intracellular calcium (Ca 2ϩ ) in neurons at risk. Maxi-K channels are large-conductance voltage-and Ca 2ϩ -activated K ϩ channel proteins (Chang et al., 1997). BMS-204352, chemically designated as (3S)-(ϩ)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one), is a maxi-K channel opener . This compound has the potential to prevent and treat ischemic stroke. The fluoro-oxyindole, BMS-204352, provided significant levels of cortical neuroprotection in rat models of stroke by augmenting an endogenous mechanism for regulating Ca 2ϩ entry and membrane potential to protect the neurons (Cheney et al., 2001;Gribkoff et al., 2001).Metabolism appeared to be predominant in the disposition of BMS-204352 in rats and dogs (Krishna et al., 2002d). Following an intraarterial infusion of [ 14 C]BMS-204352 to rats (6 mg/kg) and dogs (2 mg/kg), the AUC values of the unchanged BMS-204352 represented only a very small fraction of the plasma radioactivity. Radioactivity was primarily excreted in the feces (more than 85% of administered dose over a 7-day collection period). Within an hour of dosing rats with [14 C]BMS-204352, over two-thirds of the radioactivity in plasma is covalently ...