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

Abstract

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 ...

Disposition and Metabolism of [14C]SB-649868, an Orexin 1 and 2 Receptor Antagonist, in Humans

“…Low recovery of radioactive material from feces (and later plasma samples), together with protracted elimination of total drug-related dmd.aspetjournals.org material, would also be consistent with metabolic activation to a reactive species and subsequent binding to endogenous protein material (Zhang et al, 2005). Although no attempt was made to establish whether the binding to plasma proteins was covalent in nature, there is evidence indicating covalent binding of drug-related material to microsomal protein (based on SDS-polyacrylamide gel electrophoresis) after in vitro incubations (M. Dave, unpublished data).…”

Tissue Distribution and Identification of Radioactivity Components at Elimination Phase after Oral Administration of [14C]CS-1036, anα-Amylase Inhibitor, to Rats

“…One possible hypothesis is the covalent binding of CS-1036 metabolites to plasma proteins. Drugs that exhibit a long half-life of the radioactivity in the plasma in animals and humans are reported to be often linked with covalent binding of reactive metabolites to macromolecules in the plasma (Zhang et al, 2005). However, CS-1036 and its metabolites were not considered to exhibit covalent binding potency to plasma proteins.…”

“…In some cases, slow elimination of radioactivity after the treatment of a radiolabeled compound is caused by covalent binding to macromolecules (Zhang et al, 2005;Takakusa et al, 2008). However, the covalent binding was not expected for CS-1036, because CS-1036 had not been metabolized in the liver, kidney, and intestine.…”

Quantitative Structure–pharmacokinetics Modeling of the Unbound Clearance for Neutral Drugs

“…Clevidipine butyrate is rapidly metabolized via hydrolysis by esterases in blood and extravascular tissues [34]. Maxipost undergoes N-glucuronidation and O-dealkylation to a metabolite, covalently bound to HSA [35]. Propofol metabolizes extensively in both liver and kidney, mainly by hydroxylation and glucuronidation [36,37].…”