Tissue Distribution and Elimination of Isavuconazole following Single and Repeat Oral-Dose Administration of Isavuconazonium Sulfate to Rats

ABSTRACT Quantitative whole-body autoradiography was used to assess the distribution and tissue penetration of isavuconazole in rats following single and repeated oral-dose administration of radiolabeled isavuconazonium sulfate, the prodrug of isavuconazole. Following a single-dose administration of radiolabeled isavuconazonium sulfate (labeled on the active moiety), radioactivity was detectable within 1 h postdose in 56 of 65 tissue/fluid specimens. The highest maximum concentrations ( C max ) were observed in bile and liver (66.6 and 24.7 μg eq/g, respectively). The lowest C max values were in bone and eye lens (0.070 and 0.077 μg eq/g, respectively). By 144 h postdose, radioactivity was undetectable in all tissues/fluids except liver (undetectable at 336 h) and adrenal gland tissues (undetectable at 672 h). Following daily administration for up to 21 days, 1-h-postdose C max values were the highest on or before day 14 in all except seven tissues/fluids, of which only rectum mucosa and small intestine mucosa had C max values &gt;25% higher than all other 1-h-postdose values. For 24-h-postdose C max values, only large intestine, large intestine mucosa, and urine had the highest C max values at day 21. The penetration of single oral doses of unlabeled isavuconazole (25 mg/kg of body weight isavuconazonium sulfate) and voriconazole (50 mg/kg) into rat brain (assessed using liquid chromatography-tandem mass spectrometry) was also compared. Brain concentration/plasma concentration ratios reached approximately 1.8:1 and 2:1, respectively. These data suggest that isavuconazole penetrates most tissues rapidly, reaches a steady state in most or all tissues/fluids within 14 days, does not accumulate in tissues/fluids over time, and achieves potentially efficacious concentrations in the brain. </jats:p

DMD #22277 1 Metabolism, Pharmacokinetics and Excretion of a Cholesteryl Ester Transfer Protein Inhibitor, Torcetrapib, in Rats, Monkeys, and Mice: Characterization of Unusual and Novel Metabolites by High Resolution LC-MS/MS and 1 H NMR DMD #22277 2 IN V

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Metabolism, Distribution, and Excretion of a Next Generation Selective Estrogen Receptor Modulator, Lasofoxifene, in Rats and Monkeys

ABSTRACT: Disposition of lasofoxifene (LAS; 6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol. tartrate) was investigated in rats and monkeys after oral administration of a single oral dose of [ 14 C]LAS. Total mean recoveries of the radiocarbon were 96.7 and 94.3% from rats and monkeys, respectively. The major route of excretion in both species was the feces, and based on a separate study in the bile duct-cannulated rat, this likely reflects excretion in bile rather than incomplete absorption. Whole-body autoradioluminography suggested that [ 14 C]LAS radioequivalents distributed rapidly in the rat with most tissues achieving maximal concentrations at 1 h. Half-life of radioactivity was longest in the uvea (124 h) and shortest in the spleen (ϳ3 h). LAS was extensively metabolized in both rats and monkeys because no unchanged drug was detected in urine and/or bile. Based on area under the curve (0-24) values, &gt;78% of the circulating radioactivity was due to the metabolites. A total of 22 metabolites were tentatively identified by liquid chromatography-tandem mass spectrometry. Based on the structures of the metabolites, six metabolic pathways of LAS were identified: hydroxylation at the tetraline ring, hydroxylation at the aromatic ring attached to tetraline, methylation of the catechol intermediates by catechol-O-methyl transferase, oxidation at the pyrrolidine ring, and direct conjugation with glucuronic acid and sulfuric acid. LAS and its glucuronide conjugate (M7) were the major circulating drug-related moieties in both rats and monkeys. However, there were notable species-related qualitative and quantitative differences in the metabolic profiles. The catechol (M21) and its sulfate conjugate (M10) were observed only in monkeys, whereas the glucuronide conjugate of the methylated catechol (M8) and hydroxy-LAS (M9) were detected only in rats