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.
The absorption, metabolism, and excretion of midostaurin, a potent class III tyrosine protein kinase inhibitor for acute myelogenous leukemia, were evaluated in healthy subjects. A microemulsion formulation was chosen to optimize absorption. After a 50-mg [C]midostaurin dose, oral absorption was high (>90%) and relatively rapid. In plasma, the major circulating components were midostaurin (22%), CGP52421 (32.7%), and CGP62221 (27.7%). Long plasma half-lives were observed for midostaurin (20.3 hours), CGP52421 (495 hours), and CGP62221 (33.4 hours). Through careful mass-balance study design, the recovery achieved was good (81.6%), despite the long radioactivity half-lives. Most of the radioactive dose was recovered in feces (77.6%) mainly as metabolites, because only 3.43% was unchanged, suggesting mainly hepatic metabolism. Renal elimination was minor (4%). Midostaurin metabolism pathways involved hydroxylation, -demethylation, amide hydrolysis, and-demethylation. High plasma CGP52421 and CGP62221 exposures in humans, along with relatively potent cell-based IC for FMS-like tyrosine kinase 3-internal tandem duplications inhibition, suggested that the antileukemic activity in AML patients may also be maintained by the metabolites. Very high plasma protein binding (>99%) required equilibrium gel filtration to identify differences between humans and animals. Because midostaurin, CGP52421, and CGP62221 are metabolized mainly by CYP3A4 and are inhibitors/inducers for CYP3A, potential drug-drug interactions with mainly CYP3A4 modulators/CYP3A substrates could be expected. Given its low aqueous solubility, high oral absorption and extensive metabolism (>90%), midostaurin is a Biopharmaceutics Classification System/Biopharmaceutics Drug Disposition Classification System (BDDCS) class II drug in human, consistent with rat BDDCS in vivo data showing high absorption (>90%) and extensive metabolism (>90%).
ABSTRACT:The pharmacokinetics, absorption, metabolism, and excretion of vildagliptin, a potent and orally active inhibitor of dipeptidyl peptidase 4, were evaluated in male rats and dogs. Vildagliptin was rapidly absorbed with peak plasma concentrations occurring between 0.5 and 1.5 h. Moderate to high bioavailability was observed in both species (45-100%). The distribution and elimination halflives of vildagliptin were short: 0.57 h [82% of area under the plasma drug concentration-time curve (AUC)] and 8.8 h in the rat and 0.05 and 0.89 h (87% of AUC) in the dog, respectively. The volume of distribution was 1.6 and 8.6 l/kg in dogs and rats, respectively, indicating moderate to high tissue distribution. The plasma clearance of vildagliptin was relatively high for the rat (2.9 l/h/kg) and dog (1.3 l/h/kg) compared with their hepatic blood flow.The major circulating components in plasma after an intravenous or oral dose were the parent compound (rat and dog), a carboxylic acid metabolite from the hydrolysis of the amide bond M15.3 (dog), and a carboxylic acid metabolite from the hydrolysis of the cyano moiety M20.7 (rat and dog). After intravenous dosing, urinary excretion of radioactivity (47.6-72.4%) was the major route of elimination for rats and dogs as 18.9 to 21.3% of the dose was excreted into urine as unchanged parent drug. The recovery was good in both species (81-100% of the dose). Vildagliptin was mainly metabolized before excretion in both species. Similar to plasma, the most predominant metabolite in excreta was M20.7 in rats and dogs, and another major metabolite in dogs was M15.3.The administration of dipeptidyl peptidase IV (DPP-4) inhibitors to diabetics has been proven to augment endogenous glucagon-like peptide-1 (GLP-1) activity, which in turn produces a clinically significant lowering of diabetic glycemia comparable with that observed when GLP-1 is administered by direct infusion (Gutniak et al., 1992(Gutniak et al., , 1997Deacon et al., 1995;Mentlein, 1999;Drucker, 2003;Mest and Mentlein, 2005). Vildagliptin (Galvus, LAF237, 1-[[3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine) is a potent, orally active inhibitor of DPP-4, which has been shown to ameliorate hyperglycemia in diabetic patients by preventing the cleavage and inactivation of GLP-1. Vildagliptin is now commercially available in the European market (Villhauer et al., 2003;He et al., 2007).The IC 50 of vildagliptin against the DPP-4 enzyme is 2 nM, based on the in vitro recombinant DPP-4 assay, indicating high potency. In humans, the effect of vildagliptin on DPP-4 inhibition is reflected in an IC 50 of 4.5 nM, a value that suggests higher potency than that reported for another DPP-4 inhibitor, sitagliptin (IC 50 of 26 nM) (Herman et al., 2005;He et al., 2007). To aid in the selection of appropriate species for preclinical testing, the disposition of vildagliptin was evaluated in the rat and dog and compared with that in the human. Results from in vivo absorption, metabolism, and excretion studies in rat and dogs as wel...
Supplemental informationSynthesis of M27.5: In a 400 mL polyethylene cup the reaction buffer [30 mL, 50 mM uridine 5'-diphosphoglucuronic acid trisodium salt, 25 mM magnesium cloride, 250 mM 2-(4-(2-Hydroxyethyl)-1-piperazinyl)-ethansulfonic acid, aq. pH 7.5] was mixed with bovine liver S9 preparation (15 mL; the liver S9 fractions were prepared as described in Kittellmann M. et al 2003). Substrate solution (4 mL, 55 mM asciminib in DMSO) was added. The reaction was incubated on an orbital shaker at 37°C and 230 rpm for 16 hours. The reaction was mixed with two volume equivalents of acetonitrile:methanol mixture (50:50) and stirred at room temperature for 15 minutes. The broth was centrifuged at 8600 g for 40 min and the supernatant was filtered through a paper filter. The filtrate was mixed with 900 mL of aqueous trifluoroacetic acid 0.05 % and pumped directly on the RP18 chromatography column. The conditions for preparative HPLC were: 250 x 21 mm Nucloeodur 100-10 C18 ec column (Macherey-Nagel, Düren, Germany); solvent A: aqueous trifluoroacetic acid 0.05 %; solvent B: acetonitrile; gradient: 0 -5 min 10 % B, 40 min 95 % B, flow rate of 40 mL/min; room temperature; detection at 220 nm; fraction size 40 mL. The product containing fractions were again combined, concentrated to about 50 mL and dried by lyophilization overnight. M27.5, 65 mg (40%), was obtained with > 97 % purity (HPLC/full DAD) as a trifluoroacetic acid salt and analyzed by NMR spectroscopy.
The multitargeted protein kinase inhibitor midostaurin is approved for the treatment of both newly diagnosed FLT3-mutated acute myeloid leukemia (AML) and KIT-driven advanced systemic mastocytosis. AML is a heterogeneous malignancy, and investigational drugs targeting FLT3 have shown disparate effects in patients with FLT3-mutated AML, probably as a result of their inhibiting different targets and pathways at the administered doses. However, the efficacy and side effects of drugs do not just reflect the biochemical and pharmacodynamic properties of the parent compound but are often comprised of complex cooperative effects between the properties of the parent and active metabolites. Following chronic dosing, two midostaurin metabolites attain steady-state plasma trough levels greater than that of the parent drug. In this study, we characterized these metabolites and determined their profiles as kinase inhibitors using radiometric transphosphorylation assays. Like midostaurin, the metabolites potently inhibit mutant forms of FLT3 and KIT and several additional kinases that either are directly involved in the deregulated signaling pathways or have been implicated as playing a role in AML via stromal support, such as IGF1R, LYN, PDPK1, RET, SYK, TRKA, and VEGFR2. Consequently, a complex interplay between the kinase activities of midostaurin and its metabolites is likely to contribute to the efficacy of midostaurin in AML and helps to engender the distinctive effects of the drug compared to those of other FLT3 inhibitors in this malignancy.
1. The potential for drug-drug interactions of LCZ696 (a novel, crystalline complex comprising sacubitril and valsartan) was investigated in vitro. 2. Sacubitril was shown to be a highly permeable P-glycoprotein (P-gp) substrate and was hydrolyzed to the active anionic metabolite LBQ657 by human carboxylesterase 1 (CES1b and 1c). The multidrug resistance-associated protein 2 (MRP2) was shown to be capable of LBQ657 and valsartan transport that contributes to the elimination of either compound. 3. LBQ657 and valsartan were transported by OAT1, OAT3, OATP1B1 and OATP1B3, whereas no OAT- or OATP-mediated sacubitril transport was observed. 4. The contribution of OATP1B3 to valsartan transport (73%) was appreciably higher than that by OATP1B1 (27%), Alternatively, OATP1B1 contribution to the hepatic uptake of LBQ657 (∼70%) was higher than that by OATP1B3 (∼30%). 5. None of the compounds inhibited OCT1/OCT2, MATE1/MATE2-K, P-gp, or BCRP. Sacubitril and LBQ657 inhibited OAT3 but not OAT1, and valsartan inhibited the activity of both OAT1 and OAT3. Sacubitril and valsartan inhibited OATP1B1 and OATP1B3, whereas LBQ657 weakly inhibited OATP1B1 but not OATP1B3. 6. Drug interactions due to the inhibition of transporters are unlikely due to the redundancy of the available transport pathways (LBQ657: OATP1B1/OAT1/3 and valsartan: OATP1B3/OAT1/3) and the low therapeutic concentration of the LCZ696 analytes.
Background: AMN107, a selective and potent inhibitor of Bcr-Abl tyrosine kinase signaling, has demonstrated activity against imatinib resistant forms of Bcr-Abl in patients with chronic myelogenous leukemia at daily oral doses of ≥200 mg in a phase I clinical trial. These studies also showed dose proportional systemic exposure to drug in the 50 - 200 mg range, but progressively less than proportional increases and higher variability in drug exposure with daily doses >200 mg. The present study in healthy volunteer subjects was conducted to determine the safety, PK, metabolism, and mass balance of AMN107 to aid in the understanding of the processes that may contribute to the drug’s PK behavior and potentially impact safety and efficacy. Methods: 4 male volunteer subjects (age 23 to 46 years) received, after an overnight fast, a single oral 400 mg dose of AMN107 radiolabeled with carbon-14 to a specific activity of 0.25 μCi/mg. Quantitative urine and fecal collections, and sequential blood and serum collections for determination of levels of total radioactivity, unchanged AMN107, and AMN107 metabolites, were obtained for up to 7 days post dose. Subjects were in good health based on medical history, clinical laboratory and vital signs assessment at baseline, and were monitored for safety during the 7 days study duration and an end-of-study evaluation on day 14 post dose. Results: There were no clinically significant changes from baseline in laboratories, vital signs, and medical examination. Mild headache was noted in 3/4 subjects which resolved without intervention. Complete recovery (97.9% of dose) was achieved within 7 days, 4.4% in urine and 93.5% in feces (69% unchanged AMN107), indicating incomplete oral absorption amounting to at least 31% of dose, and rapid elimination and no significant retention of drug and metabolites in the body. Peak serum concentrations of total radioactivity and AMN107 were observed at about 4 h post dose. AMN107 represented >75% of the total serum radioactivity at all time points monitored post dose. The terminal elimination half-life of AMN107 was about 16 hours. The major circulating metabolite, a carboxylic acid derivative of AMN107, accounting for approximately 7% of serum exposure and 4% of dose elimination in feces, was formed via an AMN107 carbinol derivative, which accounted for approximately 5% of serum exposure and 4% of dose elimination in feces. Several minor metabolites resulting from oxidation of AMN107 were also detected. Metabolite profiles were similar in whole blood and serum. Conclusions: AMN107 administered as a single 400 mg oral dose to healthy volunteer subjects was safe and well tolerated. Complete recovery of single dose suggests absence of drug retention with chronic treatment. The elimination rate of AMN107 supports once or twice daily dosing, the latter representing a potential approach to increasing the absorption of the daily dose.
1. Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effective in lowering postprandial triglycerides (TG) in healthy human subjects and fasting TG in familial chylomicronemia syndrome (FCS) patients. 2. Here we present the results of human oral absorption, metabolism and excretion (AME), intravenous pharmacokinetic (PK), and in vitro studies which together provide an overall understanding of the disposition of pradigastat in humans. 3. In human in vitro systems, pradigastat is metabolized slowly to a stable acyl glucuronide (M18.4), catalyzed mainly by UDP-glucuronosyltransferases (UGT) 1A1, UGT1A3 and UGT2B7. M18.4 was observed at very low levels in human plasma. 4. In the human AME study, pradigastat was recovered in the feces as parent drug, confounding the assessment of pradigastat absorption and the important routes of elimination. However, considering pradigastat exposure after oral and intravenous dosing, this data suggests that pradigastat was completely bioavailable in the radiolabeled AME study and therefore completely absorbed. 5. Pradigastat is eliminated very slowly into the feces, presumably via the bile. Renal excretion is negligible. Oxidative metabolism is minimal. The extent to which pradigastat is eliminated via metabolism to M18.4 could not be established from these studies due to the inherent instability of glucuronides in the gastrointestinal tract.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.