ABSTRACT:The absorption, metabolism, and excretion of (1-[[3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine (vildagliptin), an orally active and highly selective dipeptidyl peptidase 4 inhibitor developed for the treatment of type 2 diabetes, were evaluated in four healthy male subjects after a single p.o. 100-mg dose of [ 14 C]vildagliptin. Serial blood and complete urine and feces were collected for 168 h postdose. Vildagliptin was rapidly absorbed, and peak plasma concentrations were attained at 1.1 h postdose. The fraction of drug absorbed was calculated to be at least 85.4%. Unchanged drug and a carboxylic acid metabolite (M20.7) were the major circulating components in plasma, accounting for 25.7% (vildagliptin) and 55% (M20.7) of total plasma radioactivity area under the curve. The terminal half-life of vildagliptin was 2.8 h. Complete recovery of the dose was achieved within 7 days, with 85.4% recovered in urine (22.6% unchanged drug) and the remainder in feces (4.54% unchanged drug). Vildagliptin was extensively metabolized via at least four pathways before excretion, with the major metabolite M20.7 resulting from cyano group hydrolysis, which is not mediated by cytochrome P450 (P450) enzymes. Minor metabolites resulted from amide bond hydrolysis (M15.3), glucuronidation (M20.2), or oxidation on the pyrrolidine moiety of vildagliptin (M20.9 and M21.6). The diverse metabolic pathways combined with a lack of significant P450 metabolism (1.6% of the dose) make vildagliptin less susceptible to potential pharmacokinetic interactions with comedications of P450 inhibitors/inducers. Furthermore, as vildagliptin is not a P450 inhibitor, it is unlikely that vildagliptin would affect the metabolic clearance of comedications metabolized by P450 enzymes.
(2017) Clinical disposition, metabolism and invitro drug-drug interaction properties of omadacycline, Xenobiotica, 47:8, 682-696, DOI: 10.1080/00498254.2016 Omadacycline was a substrate of P-glycoprotein, but not of the other transporters. 3. Omadacycline metabolic stability was confirmed in six healthy male subjects who received a single 300 mg oral dose of [ 14 C]-omadacycline (36.6 mCi). Absorption was rapid with peak radioactivity ($610 ngEq/mL) between 1-4 h in plasma or blood. The AUC last of plasma radioactivity (only quantifiable to 8 h due to low radioactivity) was 3096 ngEq h/mL and apparent terminal half-life was 11.1 h. Unchanged omadacycline reached peak plasma concentrations ($563 ng/mL) between 1-4 h. Apparent plasma half-life was 17.6 h with biphasic elimination. Plasma exposure (AUC inf ) averaged 9418 ng h/mL, with high clearance (CL/F, 32.8 L/h) and volume of distribution (Vz/F 828 L). No plasma metabolites were observed. 4. Radioactivity recovery of the administered dose in excreta was complete (>95%); renal and fecal elimination were 14.4% and 81.1%, respectively. No metabolites were observed in urine or feces, only the omadacycline C4-epimer.
ABSTRACT:Lumiracoxib (Prexige; 2-[(2-fluoro-6-chlorophenyl)amino]-5-methyl-benzeneacetic acid) is a novel, chemically distinct cyclooxygenase-2 selective inhibitor, which has been developed for the treatment of osteoarthritis, rheumatoid arthritis, and acute pain. The absorption, metabolism, disposition, and mass balance of [ 14 C]lumiracoxib were investigated in four healthy male subjects after a single 400-mg oral dose. Serial blood and complete urine and feces were collected for 168 h postdose. Lumiracoxib was rapidly absorbed, achieving mean plasma concentrations >1 g/ml within 1 h of dosing. Unchanged drug in plasma accounted for 81 to 91% of radioactivity up to 2.5 h postdose, suggesting a modest firstpass effect; unchanged drug was the major circulating component in plasma, accounting for ϳ43% of the AUC 0 to 24h . The terminal half-life of lumiracoxib in plasma was 6.5 h. Major plasma metabolites were the 5-carboxy, 4-hydroxy, and 4-hydroxy-5-carboxy derivatives. Excretion involved both renal (54.1%) and fecal (42.7%) routes, and dose recovery was almost complete (96.8%). Lumiracoxib was extensively metabolized before excretion, with little unchanged drug in urine (3.3% of dose) or feces (2.0% of dose). The major metabolic pathways of lumiracoxib were oxidation of the 5-methyl group and hydroxylation of the dihaloaromatic ring. Glucuronic acid conjugates of lumiracoxib metabolites (and to a minor extent lumiracoxib itself) were identified, although there was no evidence of cysteine, mercapturic acid, or glutathione conjugates. In summary, orally administered lumiracoxib is rapidly absorbed and undergoes extensive metabolism before excretion via urine and feces, with no evidence of formation of potentially reactive metabolites.
Peptide deformylase (PDF) is a prokaryotic metalloenzyme that is essential for bacterial growth and is a new target for the development of antibacterial agents. All previously reported PDF inhibitors with sufficient antibacterial activity share the structural feature of a 2-substituted alkanoyl at the P 1 site. Using a combination of iterative parallel synthesis and traditional medicinal chemistry, we have identified a new class of PDF inhibitors with N-alkyl urea at the P 1 site. Compounds with MICs of <4 g/ml against gram-positive and gram-negative pathogens, including Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae, have been identified. The concentrations needed to inhibit 50% of enzyme activity (IC 50 s) for Escherichia coli Ni-PDF were <0.1 M, demonstrating the specificity of the inhibitors. In addition, these compounds were very selective for PDF, with IC 50 s of consistently >200 M for matrilysin and other mammalian metalloproteases. Structure-activity relationship analysis identified preferred substitutions resulting in improved potency and decreased cytotoxity. One of the compounds (VRC4307) was cocrystallized with PDF, and the enzymeinhibitor structure was determined at a resolution of 1.7 Å. This structural information indicated that the urea compounds adopt a binding position similar to that previously determined for succinate hydroxamates. Two compounds, VRC4232 and VRC4307, displayed in vivo efficacy in a mouse protection assay, with 50% protective doses of 30.8 and 17.9 mg/kg of body weight, respectively. These N-alkyl urea hydroxamic acids provide a starting point for identifying new PDF inhibitors that can serve as antimicrobial agents.
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