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Matthew Hoffmann Claudia Kasserra Josephine Reyes Peter Schafer Jolanta Kosek Lori Capone Anastasia Parton Heasook Kim-Kang Sekhar Surapaneni Gondi Kumar 《Cancer chemotherapy and pharmacology》2013,71(2):489-501
Purpose
To investigate the pharmacokinetics and disposition of [14C]pomalidomide following a single oral dose to healthy male subjects.Methods
Eight subjects were administered a single 2 mg oral suspension of [14C]pomalidomide. Blood (plasma), urine and feces were collected. Mass balance of radioactivity and the pharmacokinetics of radioactivity, pomalidomide and metabolites were determined. Metabolite profiling and characterization was performed. The enzymes involved in pomalidomide metabolism and the potential pharmacological activity of metabolites were evaluated in vitro.Results
Mean recovery was 88 %, with 73 and 15 % of the radioactive dose excreted in urine and feces, respectively, indicating good oral absorption. Mean C max, AUC0?∞ and t max values for pomalidomide in plasma were 13 ng/mL, 189 ng*h/mL and 3.0 h. Radioactivity and pomalidomide were rapidly cleared from circulation, with terminal half-lives of 8.9 and 11.2 h. Pomalidomide accounted for 70 % of the circulating radioactivity, and no circulating metabolite was present at >10 % of parent compound. Pomalidomide was extensively metabolized prior to excretion, with excreted metabolites being similar to those observed in circulation. Clearance pathways included cytochrome P450-mediated hydroxylation with subsequent glucuronidation (43 % of the dose), glutarimide ring hydrolysis (25 %) and excretion of unchanged drug (10 %). 5-Hydroxy pomalidomide, the notable oxidative metabolite, was formed primarily via CYP1A2 and CYP3A4. The hydroxy metabolites and hydrolysis products were at least 26-fold less pharmacologically active than pomalidomide in vitro.Conclusions
Following oral administration, pomalidomide was well absorbed, with parent compound being the predominant circulating component. Pomalidomide was extensively metabolized prior to excretion, and metabolites were eliminated primarily in urine. 相似文献2.
H Kim-Kang S G Gilbert A W Malick J B Johnson 《Journal of pharmaceutical sciences》1990,79(2):120-123
The compatibility of the pharmaceutical product with packaging materials is an important parameter which must be evaluated during the product development process. This paper discusses the possibility that pertinent FDA methodology can be modified in a more efficient way using currently available analytical techniques. Several studies on potential migrants from packaging materials, such as heat-seal adhesives, amber polyethylene terephthalate (PET) containers, and rubber gaskets of aerosol valves, are presented to show that commonly encountered questions with regard to packaging materials used during product stability studies can also be answered in the same way. 相似文献
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Potential migrants were isolated from commercial polyethylene terephthalate (PET) bottles using Soxhlet extraction. The concentrated extract was then subjected to GC/MS analysis. A total of 19 migrants has been identified. The majority of compounds appeared to be intermediate reaction products or residual monomers of their dehydration and transesterification products. Several processing aids such as fatty acids and commonly used plasticizers were also identified. The amount of seven compounds present in the major portion of exhaustive extract of the PET bottle wall ranged from 800 µg/g polymer to as low as 0.6 µg/g. 相似文献
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Ryan H. Takahashi Shuguang Ma Qin Yue Heasook Kim-Kang Yijun Yi Justin Ly 《Xenobiotica; the fate of foreign compounds in biological systems》2017,47(1):50-65
1.?The absorption, metabolism and excretion of cobimetinib, an allosteric inhibitor of MEK1/2, was characterized in mass balance studies following single oral administration of radiolabeled (14C) cobimetinib to Sprague–Dawley rats (30?mg/kg) and Beagle dogs (5?mg/kg).2.?The oral dose of cobimetinib was well absorbed (81% and 71% in rats and dogs, respectively). The maximal plasma concentrations for cobimetinib and total radioactivity were reached at 2–3?h post-dose. Drug-derived radioactivity was fully recovered (~90% of the administered dose) with the majority eliminated in feces via biliary excretion (78% of the dose for rats and 65% for dogs). The recoveries were nearly complete after the first 48?h following dosing.3.?The metabolic profiles indicated extensive metabolism of cobimetinib prior to its elimination. For rats, the predominant metabolic pathway was hydroxylation at the aromatic core. Lower exposures for cobimetinib and total radioactivity were observed in male rats compared with female rats, which was consistent to in vitro higher clearance of cobimetinib for male rats. For dogs, sequential oxidative reactions occurred at the aliphatic portion of the molecule. Though rat metabolism was well-predicted in vitro with liver microsomes, dog metabolism was not.4.?Rats and dogs were exposed to the two major human circulating Phase II metabolites, which provided relevant metabolite safety assessment. In general, the extensive sequential oxidative metabolism in dogs, and not the aromatic hydroxylation in rats, was more indicative of the metabolism of cobimetinib in humans. 相似文献
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