ABSTRACT:The distribution, metabolism, and elimination of intravenous [ 14 C]clofarabine was studied in Fischer 344 male rats under a once daily for 5 days dosing schedule of 25 or 50 mg/kg/day. Also, the in vitro metabolism in rat, dog, and human hepatocytes was studied. Plasma radioactivity (of which clofarabine accounted for 63% to 93%) exhibited three phases of exponential elimination, with half-lives of 0.3, 1.3, and 12.8 h after administration of the 25 mg/kg/day regimen. Unscheduled deaths occurred after one to three doses with the 50 mg/kg regimen, possibly due to nonlinear pharmacokinetics; therefore, mass balance and radiokinetic profiles could not be obtained. A total of 77.1% (of which 87.2% was clofarabine) and 10.8% (of which 6.9% was clofarabine) of the dose was recovered in urine and feces, respectively. 6-Ketoclofarabine, believed to be formed via adenosine deaminase, was the metabolite of greatest concentration found in urine and feces, but in each matrix, it accounted for only 7% of the daily recovery of radioactivity. 6-Ketoclofarabine was also found in myocardium and liver but accounted for less than 2% of the total radioactivity in those tissues. Clofarabine was the major analyte found in myocardium (>97% region of integration) and liver (>94% region of integration). Whole body autoradiography demonstrated that the highest postdistributive concentrations of radioactivity were in the excretory organs, kidney, bladder, and gastrointestinal tract, with no remarkable suborgan distribution. In rat, dog, and human hepatocytes, 95, 96, and 99.8% [ 14 C]clofarabine remained, respectively, after 6 h of incubation. Eleven metabolites were observed, with the largest constituting 2.5% of the radioactivity.Clofarabine ( Fig. 1; 2-chloro-2Ј-fluoro-deoxy-9--D-arabinofuranosyladenine) is a next-generation nucleoside analog being developed for the treatment of solid and hematologic tumors. Clofarabine is a nucleoside prodrug that must be intracellularly metabolized to its mono-, di-, and then, finally, triphosphate conjugate for activity to be observed. At the cellular level, it is postulated that clofarabine triphosphate has multiple mechanisms of action: 1) inhibition of DNA polymerase ␣; 2) inhibition of ribonucleotide reductase; and 3) disruption of mitochondrial function through release of cytochrome c and proapoptotic proteins.The additive effect of these parallel events leads to the depletion of intracellular deoxynucleotide triphosphate pools, inhibition of elongation of DNA strands during synthesis, and release of proapoptotic mitochondrial factors in both actively dividing and quiescent tumor cells, leading to programmed cell death (Parker et al., 1991;Xie and Plunkett, 1996). Previous studies in adults have shown clofarabine activity in both solid tumors and hematologic malignancies. Kantarjian et al. (2003b) administered clofarabine by 1-h intravenous infusion once daily for 5 days in a phase I dose-escalation study. The maximum tolerated dose (MTD) in adult patients with solid tumors was 2 mg/...
Historical agriculture and present-day fire regimes can have significant effects on contemporary ecosystems. Although past agricultural land use can lead to long-term changes in plant communities, it remains unclear whether these persistent land-use legacies alter plant-consumer interactions, such as seed predation, and whether contemporary disturbance (e.g., fire) alters the effects of historical agriculture on these interactions. We conducted a study at 27 sites distributed across 80,300 ha in post-agricultural and non-agricultural longleaf pine woodlands with different degrees of fire frequency to test the hypothesis that past and present-day disturbances that alter plant communities can subsequently alter seed predation. We quantified seed removal by arthropods and rodents for Tephrosia virginiana and Vernonia angustifolia, species of conservation interest. We found that the effects of land-use history and fire frequency on seed removal were contingent on granivore guild and microhabitat characteristics. Tephrosia virginiana removal was greater in low fire frequency sites, due to greater seed removal by rodents. Although overall removal of V. angustifolia did not differ among habitats, rodents removed more seeds than arthropods at post-agricultural sites and non-agricultural sites with low fire frequencies, but not at non-agricultural sites with high fire frequencies. Land-use history and fire frequency also affected the relationship between microhabitat characteristics and removal of V. angustifolia. Our results suggest that historical agriculture and present-day fire regimes may alter seed predation by shifting the impact of rodent and arthropod seed predators among habitats, with potential consequences for the establishment of rare plant species consumed by one or both predators.
Ecological restoration is a global priority, with potential to reverse biodiversity declines and promote ecosystem functioning. Yet, successful restoration is challenged by lingering legacies of past land-use activities, which are pervasive on lands available for restoration. Although legacies can persist for centuries following cessation of human land uses such as agriculture, we currently lack understanding of how land-use legacies affect entire ecosystems, how they influence restoration outcomes, or whether restoration can mitigate legacy effects. Using a large-scale experiment, we evaluated how restoration by tree thinning and land-use legacies from prior cultivation and subsequent conversion to pine plantations affect fire-suppressed longleaf pine savannas. We evaluated 45 ecological properties across four categories: 1) abiotic attributes, 2) organism abundances, 3) species diversity, and 4) species interactions. The effects of restoration and land-use legacies were pervasive, shaping all categories of properties, with restoration effects roughly twice the magnitude of legacy effects. Restoration effects were of comparable magnitude in savannas with and without a history of intensive human land use; however, restoration did not mitigate numerous legacy effects present prior to restoration. As a result, savannas with a history of intensive human land use supported altered properties, especially related to soils, even after restoration. The signature of past human land-use activities can be remarkably persistent in the face of intensive restoration, influencing the outcome of restoration across diverse ecological properties. Understanding and mitigating land-use legacies will maximize the potential to restore degraded ecosystems.
The pharmacokinetics, metabolism, and excretion of ciclesonide, a novel and effective inhaled glucocorticoid for the treatment of asthma, were investigated after intravenous and oral administration of 14C-ciclesonide in the mouse, rat, rabbit, and dog. The pharmacokinetics of ciclesonide in all animal species were characterized by a low oral bioavailability (approximately 6% or less), a high clearance, and a large volume of distribution. The apparent terminal half-life of ciclesonide was short; the apparent terminal half-life of the active desisobutyryl-ciclesonide metabolite (des-CIC or M1) was longer and ranged from 2.4 to 6.9 hours in the 4 species. Metabolites derived from ciclesonide in serum (or plasma) and excreta samples from the 4 animal species were profiled and identified by LC/RAM/MS (liquid chromatography/radioactivity monitor/mass spectrometry). Ciclesonide was extensively metabolized to yield des-CIC, which was further metabolized to primarily yield hippuric acid and hydroxylated metabolites, namely, isomers of cyclohexane-monohydroxylated des-CIC and B-ring-monohydroxylated des-CIC. Greater than 90% of intravenous and oral 14C-ciclesonide doses were recovered in all species; the main elimination route was fecal/biliary. A comparison of in vitro and in vivo metabolite profiles between mice, rats, rabbits, and dogs with those from humans indicated that metabolic pathways for ciclesonide were qualitatively similar in humans and in the 4 animal species.
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.