Evidence for episodic acidification effects on migrating Atlantic salmon Salmo salar smolts.

Field studies were conducted to determine levels of gill aluminium as an index of acidification effects on migrating Atlantic salmon Salmo salar smolts in the north-eastern U.S.A. along mainstem river migration corridors in several major river basins. Smolts emigrating from the Connecticut River, where most (but not all) tributaries were well buffered, had low or undetectable levels of gill aluminium and high gill Na(+) /K(+) -ATPase (NKA) activity. In contrast, smolts emigrating from the upper Merrimack River basin where most tributaries are characterized by low pH and high inorganic aluminium had consistently elevated gill aluminium and lower gill NKA activity, which may explain the low adult return rates of S. salar stocked into the upper Merrimack catchment. In the Sheepscot, Narraguagus and Penobscot Rivers in Maine, river and year-specific effects on gill aluminium were detected that appeared to be driven by underlying geology and high spring discharge. The results indicate that episodic acidification is affecting S. salar smolts in poorly buffered streams in New England and may help explain variation in S. salar survival and abundance among rivers and among years, with implications for the conservation and recovery of S. salar in the north-eastern U.S.A. These results suggest that the physiological condition of outmigrating smolts may serve as a large-scale sentinel of landscape-level recovery of atmospheric pollution in this and other parts of the North Atlantic region.

Quality of life during the course of cancer treatment in older newly diagnosed patients. Results of a prospective pilot study.

BACKGROUND: The aim of this prospective study was to report the quality of life (QoL) of older cancer patients during the first year after diagnosis and factors influencing QoL. PATIENTS AND METHODS: Newly diagnosed patients aged ≥65 years were recruited for a pilot prospective cohort study at the Jewish General Hospital, Montreal, Canada. Participants were interviewed at baseline, and at 1.5, 3, 4.5, 6, and 12 months. QoL was assessed at each interview using the European Organization for the Research and Treatment of Cancer Quality of Life Core Questionnaire with 30 items. Logistic regression was conducted to determine which sociodemographic, health, and functional status characteristics were associated with decline in global health status/QoL between baseline and 12-month follow-up. RESULTS: There were 112 participants at baseline (response rate 72%), median age of 74.1, and 70% were women. Between baseline and 12-month follow-up (n=78), 18 participants (23.1%) declined ≥10 points in global health status/QoL, while 34 participants (43.6%) remained stable and 23 participants (33.3%) improved ≥10 points. None of the sociodemographic, health, and functional status variables were associated with decline in logistic regression analyses. CONCLUSION: Almost 25% of older adults experienced clinically relevant decline in their QoL. Further research is needed on which factors influence decline in QoL in older adults.

A study of 17beta-estradiol-regulated genes in the vagina of postmenopausal women with vaginal atrophy.

BACKGROUND: Vaginal atrophy (VA) is a prevalent disorder in postmenopausal women that is characterized by decreased epithelial thickness, reduced vaginal maturation index (VMI) and increased vaginal pH. Current medical therapy consists of local or systemic replacement of estrogens. OBJECTIVE: The goal of this study was to understand, at a molecular level, the effect of estradiol (E2) on the vaginal epithelium. METHODS: Nineteen women were treated with E2 delivered through a skin patch at a dose of 0.05mg/day for 12 weeks. The diagnosis of VA was confirmed by a VMI with < or =5% superficial cells and vaginal pH>5.0. Vaginal biopsy samples were collected at baseline and after treatment. Differentially expressed mRNA transcripts in these biopsies were determined by microarray analysis. RESULTS: All 19 subjects had increased VMI (>5%) and/or reduced pH (< or =5) following treatment. Most subjects also had increased serum E2 levels and reduced serum FSH levels. Transcriptional profiling of vaginal biopsies identified over 3000 E2-regulated genes, including those involved in several key pathways known to regulate cell growth and proliferation, barrier function and pathogen defense. CONCLUSIONS: E2 controls a plethora of cellular pathways that are concordant with its profound effect on vaginal physiology. The data presented here are a useful step toward understanding the role of E2 in vaginal tissue and the development of novel therapeutics for the treatment of VA.

Molecular classification of Crohn's disease and ulcerative colitis patients using transcriptional profiles in peripheral blood mononuclear cells.

Ulcerative colitis (UC) and Crohn's disease (CD) are common inflammatory bowel diseases producing intestinal inflammation and tissue damage. Although emerging evidence suggests these diseases are distinct, approximately 10% of patients remain classified as indeterminate inflammatory bowel disease even after invasive colonoscopy intended for diagnosis. A molecular diagnostic assay using a clinically accessible tissue would greatly assist in the classification of these diseases. In the present study we assessed transcriptional profiles in peripheral blood mononuclear cells from 42 healthy individuals, 59 CD patients, and 26 UC patients by hybridization to microarrays interrogating more than 22,000 sequences. Supervised analysis identified a set of 12 genes that distinguished UC and CD patient samples with high accuracy. The alterations in transcript levels observed by microarray were verified by real-time polymerase chain reaction. The results suggest that a peripheral blood mononuclear cell-based gene expression signature can provide a molecular biomarker that can complement the standard diagnosis of UC and CD.

Effect of cholesterol on the polymorphism of dipalmitoylphosphatidylcholine/melittin complexes: an NMR study.

In order to get insights into the effects of cholesterol on protein activity, the lytic power of melittin on 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/cholesterol mixtures was studied using solid-state deuterium and phosphorus-31 nuclear magnetic resonance spectroscopy (2H and 31P-NMR). After incubation, melittin disrupts pure DPPC vesicles, leading to the formation of small lipid/peptide complexes below the phase transition temperature (Tm), whereas large bilayer assemblies are reformed above Tm; the transition between these two species is thermally reversible. This study reveals that cholesterol modifies this thermal behavior and that this modulation of the lytic power of melittin is indirect, since it is essentially related to the original effect of the sterol on the thermotropism of pure lipid bilayers. It is known that melittin does not lyse gel phase DPPC bilayers spontaneously. Our study shows that the addition of large amounts of sterol (30 mol%) does not promote the spontaneous lysis at 26 degrees C, despite the increased fluidity of the lipid system. The lysis takes place around 32 degrees C, regardless of the cholesterol concentration. This study also shows that high concentrations of cholesterol (> or = 30%) in DPPC bilayer inhibit the lysis. It is proposed that the tight lipid packing due to high cholesterol concentrations prevents the penetration of melittin into the bilayer. When melittin interacts with cholesterol-rich bilayers (30 mol%), the lysis is only partial, and leads to the formation of small cholesterol-depleted particles. Finally, DPPC which bears deuteriated acyl chains was used to determine the influence of melittin on the orientational order of the lipid chains in the large assemblies. The quadrupolar splittings obtained in the presence of melittin are not considerably different than those obtained in the absence of melittin.

The influence of age and sex on the clearance of cytochrome P450 3A substrates.

Cytochrome P450s (CYPs) are an important family of enzymes in the metabolism of many therapeutic agents and endogenous metabolic reactions. The CYP3A subfamily is especially prominent in these metabolic activities. This review article focuses on how the factors of age and sex may influence the in vivo activity of human CYP3A. The functional activity of CYP3A varies based on issues such as interaction with one or more substrates and between individuals and/or localisation. For CYP3A substrates, intrinsic clearance is the component of total clearance that is contributed by the enzymes. Depending on the route of administration and the contribution of hepatic blood flow to overall clearance, sensitivities to changes in CYP3A activities may differ. Additionally, age may influence the hepatic blood flow and, in turn, affect CYP3A activity. A review of the literature regarding age influences on the clearance of CYP3A substrates does suggest that age can affect the clearance of certain CYP3A substrates.CYP3A is responsible for a large number of endogenous metabolic reactions involving steroid hormones, and enzyme activity has been reported to be induced and/or inhibited in the presence of some sex steroids. Based on published studies for most CYP3A substrates, sex does not appear to influence clearance; however, with certain substrates significant sex-related differences are found. In such cases, women primarily have higher clearance than men.

A single administration of recombinant human interleukin-12 is associated with increased expression levels of interferon-gamma and signal transducer and activator of transcription in healthy subjects.

The objectives of this study were to assess the safety and tolerability of single doses of 1, 4, and 8 mug of recombinant human interleukin-12 (rhIL-12) administered subcutaneously to healthy subjects. The pharmacokinetics, pharmacodynamics, and pharmacogenomics of rhIL-12 were evaluated. Recombinant human IL-12 was well tolerated in these healthy male and female subjects. The most frequently reported adverse events were flu-like symptoms, which exhibited a dose-response relationship. Pharmacokinetic analysis suggested that serum IL-12 levels increased with dose. Analysis of serum levels indicated that interferon-gamma increased with the dose of rhIL-12, whereas IL-6 levels showed no changes with rhIL-12 treatment. The messenger ribonucleic acid expression of signal transducer and activator of transcription was significantly increased 24 hours after the administration of rhIL-12 for all dose groups versus placebo, and results indicated that the magnitude of increase may be dose dependent. This study suggests that interferon-gamma and signal transducer and activator of transcription are biomarkers of rhIL-12 activity.

Solid-state NMR characterization and determination of the orientational order of a nematogen.

Thermotropic liquid crystalline compounds are of considerable importance due to their potential applications as advanced functional materials. A mesogen consisting of a terminal dimethylamino group, which can act as a charge-transfer donor, is particularly valuable for its light emission and nonlinear optical properties. In this study, we report the solid-state NMR investigation of the nematic behavior of one such novel mesogen (4-(dodecyloxy)benzoic acid 4-[((4-(dimethylamino)phenyl)imino)methyl]phenyl ester). Static and MAS experiments were performed on nematic and crystalline phases of the compound to measure (13)C chemical shift, (13)C-(1)H dipolar coupling, and (1)H chemical shift values. 2D chemical shift correlation of (1)H and (13)C nuclei confirmed the (13)C chemical shift values determined from 1D CPMAS experiments. The appearance of more peaks in both CPMAS and (13)C-(1)H HETCOR spectra of a crystalline solid suggests the heterogeneous orientations of phenyl rings of the mesogenic core. Variable-temperature experiments infer the motional averaging of these orientations before melting. The (1)H-(13)C dipolar coupling values, measured by 2D PITANSEMA experiments, were used to determine the orientational order of the mesogenic core at various temperatures. The influence of the linking unit and terminal substituents on the order parameter values of the mesogenic core is discussed.

Cigarette smoking enhances increased urine albumin excretion as a risk factor for glomerular filtration rate decline in primary hypertension.

BACKGROUND: Subjects with severe compared with mild primary hypertension are at greater risk for decline in glomerular filtration rate (GFR), but additional risk factors are poorly defined. METHODS: Seventy-five subjects referred for assistance with blood pressure control ("severe") and 150 not-referred hypertensive subjects ("mild") were prospectively followed for 7 years. The primary outcome was the change in calculated GFR during follow-up as predicted by various clinical parameters, including urine albumin excretion measured as urine albumin (mg)-to-creatinine (g) (alb/cr) ratio. RESULTS: Calculated GFR declined faster (more negative slope) in patients with severe hypertension than in those with mild hypertension (-0.188+/- 0.025 versus -0.120+/- 0.008 mL/min/month; P=0.010), despite similar follow-up systolic blood pressure (133.4+/-1.2 versus 131.9+/-0.8 mm Hg). Severe subjects had higher entry alb/cr (241.3+/- 29.1 versus 11.4+/- 0.5) and a greater proportion of cigarette smokers than mild subjects (56 versus 19%). Regression analysis comparing GFR decline to alb/cr showed that GFR changed minimally for alb/cr up to 200 but declined at a progressively faster rate as alb/cr increased above 200. GFR declined faster (more negative slope) in smokers than in nonsmokers (-0.231+/- 0.023 versus -0.102+/- 0.008 mL/min/month; P<0.001). Cigarette smoking increased the risk for GFR decline in subjects with alb/cr <200 and in those with alb/cr >200, but the effect was much more robust for subjects with alb/cr >200. CONCLUSIONS: Urine alb/cr >200 increases the risk for subsequent GFR decline in primary hypertension, and this risk is enhanced by cigarette smoking.

Effects of ketoconazole or rifampin on the pharmacokinetics of tivozanib hydrochloride, a vascular endothelial growth factor receptor tyrosine kinase inhibitor.

The vascular endothelial growth factor (VEGF) pathway is associated with the promotion of endothelial cell proliferation, migration, and survival necessary for angiogenesis. VEGF and its three receptor isoforms are often overexpressed in many human solid tumors. Tivozanib is a potent, selective inhibitor of VEGF receptors 1, 2, and 3, with a long half-life. The purpose of these studies was to evaluate the effect of ketoconazole, a potent inhibitor of CYP3A4, and rifampin, a potent inducer of CYP3A4, on the pharmacokinetics of tivozanib. Two phase I, open-label, 2-period, single-sequence studies evaluated the effect of steady-state ketoconazole (NCT01363778) or rifampin (NCT01363804) on the pharmacokinetic profile, safety, and tolerability of a single oral 1.5-mg dose of tivozanib. Tivozanib was well tolerated in both studies. Steady-state ketoconazole did not cause a clinically significant change in the pharmacokinetics of a single dose of tivozanib; therefore, dosing of tivozanib with a CYP3A4 pathway inhibitor should not cause a clinically significant change in serum tivozanib levels. However, coadministration of tivozanib with rifampin caused a significant decrease in the area under the curve from 0 to infinity and half-life and an increase in clearance of tivozanib, which suggest increased clearance via the enhanced CYP3A4-mediated metabolism of tivozanib.

A phase Ib study of the VEGF receptor tyrosine kinase inhibitor tivozanib and modified FOLFOX-6 in patients with advanced gastrointestinal malignancies.

BACKGROUND: Tivozanib hydrochloride (tivozanib) is a potent and selective tyrosine kinase inhibitor of all 3 vascular endothelial growth factor receptors with antitumor activity additive to 5-fluorouracil in preclinical models. This study was conducted to determine maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PKs), and antitumor activity of escalating doses of tivozanib with a modified (m)FOLFOX-6 (leucovorin, 5-fluorouracil [5-FU], and 85 mg/kg(2) oxaliplatin) regimen in patients with advanced gastrointestinal tumors. PATIENTS AND METHODS: Tivozanib was administered orally once daily for 21 days in 28-day cycles, with mFOLFOX-6 administered every 14 days. Patients were allowed to continue tivozanib after discontinuation of mFOLFOX-6. RESULTS: Thirty patients were assigned to tivozanib 0.5 mg (n = 9), 1.0 mg (n = 3), or 1.5 mg (n = 18) with mFOLFOX-6. Patients received a median of 5.2 (range, 0.03-26.9) months of tivozanib. DLTs were observed in 2 patients: Grade 3/4 transaminase level increases with tivozanib 0.5 mg, and Grade 3 dizziness with tivozanib 1.5 mg. Other Grade 3/4 adverse events included hypertension (n = 8), fatigue (n = 8), and neutropenia (n = 6). MTD for tivozanib with mFOLFOX-6 was confirmed as 1.5 mg. No PK interactions between tivozanib and mFOLFOX-6 were observed. One patient had an ongoing clinical complete response, 10 had a partial response, and 11 obtained prolonged stable disease. CONCLUSION: Tivozanib and mFOLFOX-6 is feasible and appears to be safe. The recommended dose for tivozanib with mFOLFOX-6 is 1.5 mg/d. Observed clinical activity merits further exploration in gastrointestinal tumors.

Structure of a malaria parasite antigenic determinant displayed on filamentous bacteriophage determined by NMR spectroscopy: implications for the structure of continuous peptide epitopes of proteins.

The NANP repeating sequence of the circumsporozoite protein of Plasmodium falciparum was displayed on the surface of fd filamentous bacteriophage as a 12-residue insert (NANP)(3) in the N-terminal region of the major coat protein (pVIII). The structure of the epitope determined by multidimensional solution NMR spectroscopy of the modified pVIII protein in lipid micelles was shown to be a twofold repeat of an extended and non-hydrogen-bonded loop based on the sequence NPNA, demonstrating that the repeating sequence is NPNA, not NANP. Further, high resolution solid-state NMR spectra of intact hybrid virions containing the modified pVIII proteins demonstrate that the peptides displayed on the surface of the virion adopt a single, stable conformation; this is consistent with their pronounced immunogenicity as well as their ability to mimic the antigenicity of their native parent proteins.

The antiparasitic moxidectin: safety, tolerability, and pharmacokinetics in humans.

A study in healthy male volunteers was completed to evaluate the safety, tolerability, and pharmacokinetics of a single oral dose of the antiparasitic moxidectin (MOX). This drug is registered worldwide as a veterinary antiparasitic agent for use in companion and farm animals. This is the first study of MOX in humans. All subjects were between the ages of 18 and 45 years, with normal cardiac, hematologic, hepatic, and renal function. Doses of MOX studied were 3, 9, 18, and 36 mg in cohorts of 6 subjects each (5:1, MOX:placebo). At the 9-mg and 36-mg doses, two separate cohorts were completed, one in the fasted state and one after the consumption of a high-fat breakfast. For all other cohorts, administration was in the fasted state. Safety and tolerability were assessed by physical examinations, ongoing evaluation of adverse events (AEs), and measurement of laboratory values. Pharmacokinetic (PK) samples were collected just prior to dosing and at various time points until 80 days postdose. Safety assessments from all dose groups studied suggested that MOX was generally safe and well tolerated, with a slightly higher incidence of transient, mild, and moderate central nervous system AEs as the dose increased as compared to placebo. The PKs of MOX were dose proportional within the dose range studied, and the elimination half-life (t1/2 elim) was long (mean: 20.2-35.1 days). At the 9-mg and 36-mg doses, a high-fat breakfast was shown to delay and increase the overall absorption but did not increase maximal concentrations when compared to administration in the fasted state. In summary, the results from this study indicate that MOX is safe and well tolerated in humans between the doses of 3 mg and 36 mg.

Multiple-dose, safety, pharmacokinetics, and pharmacodynamics of a new selective estrogen receptor modulator, ERA-923, in healthy postmenopausal women.

ERA-923 is a new selective estrogen receptor modulator under clinical investigation for use in tamoxifen refractory metastatic breast cancer. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of once-daily oral ERA-923 (10-200 mg) for 28 days in healthy postmenopausal females. ERA-923 was well tolerated, and adverse events were mild and reversible. No clinically significant changes in laboratory values were found with ERA-923 versus placebo. ERA-923 appeared to undergo extensive metabolism and enterohepatic recirculation. In addition, pharmacokinetic analysis showed that a high-fat breakfast increased the extent of absorption. ERA-923-dosed subjects had no uterine or ovarian changes when evaluated with transvaginal ultrasound and compared to placebo subjects. Overall, ERA-923 was safe and well tolerated in postmenopausal women dosed for 28 days.

Reliability, validity, and applicability of the Quebec User Evaluation of Satisfaction with assistive Technology (QUEST 2.0) for adults with multiple sclerosis.

PURPOSE: To investigate the measurement properties of the Quebec User Evaluation of Satisfaction with assistive Technology (QUEST 2.0) with respect to test-retest stability, alternate form reliability, construct validity and applicability. METHOD: Data on satisfaction and quality of life impacts of mobility devices were obtained from 81 community-based adults with Multiple Sclerosis, using the QUEST 2.0 and the Psychosocial Impact of Assistive Devices Scale (PIADS). Subjects were assigned to four groups and a second QUEST 2.0 was administered one week later. Groups differed with respect to the format and the order in which alternate forms were presented. Measures of association were calculated between QUEST 2.0 and PIADS (n = 81) and between QUEST 2.0 alternate forms (n = 48). Respondents' reactions were considered. RESULTS: The device subscale, services subscale, and total QUEST 2.0 scores achieved good test-retest stability (ICC 0.82, 0.82, 0.91). Alternate-form equivalence (ICC 0.89, 0.76, 0.91) was lower for services. The positive correlations between QUEST 2.0 and the three PIADS dimensions were fair to moderate for device and total QUEST 2.0 (r(p) 0.34 to 0.45) and fair with services (r(p) 0.27 to 0.30). The tool was positively received, with some restrictions for the services subscale. CONCLUSIONS: These findings on the psychometric properties of the QUEST 2.0 reinforce the relevance of the device subscale as an important outcome measure for assistive technology MS users. Further assessment of the services subscale is needed.

Ambulation aid use during the rehabilitation of people with lower limb amputations.

Our objective was to describe the progression of ambulation aid use by people with lower limb amputations during their initial rehabilitation. We prospectively studied 37 people with recent lower limb amputations and a mean (SD) age of 68 (13) years. Subjects were evaluated each weekday during gait-training physiotherapy sessions, and the type and order of ambulation aids used during ambulation training were documented. The total number of gait-training sessions that we observed was 605, with a mean (SD) of 16.4 (7.7) sessions per participant and a range of 5-47. Of the 37 participants, 33 (89%) were discharged with prostheses. The mean (SD) number of aids per person was 2.9 (1.0). The percentage of participants who used each aid (presented in the mean order in which they were first used) were 76% parallel bars, 60% four-footed walkers, 81% two-wheeled walkers, 11% two crutches, 8% four-wheeled walkers, 46% two canes, and 14% one cane. People with lower limb amputations generally use a number of ambulation aids in a fairly consistent order as they progress through their initial rehabilitation. These findings have implications for the process of providing ambulation aids and provide a foundation for further study.

The effect of food on the pharmacokinetics of tivozanib hydrochloride.

Tivozanib hydrochloride (tivozanib) is a potent, selective tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1, 2, and 3, with a long half-life. This Phase I study evaluated the effect of food on tivozanib pharmacokinetics (PK). A single oral dose of tivozanib was administered to healthy subjects in a fasted/fed and a fed/fasted state. Thirty subjects enrolled; 29 completed the study. Maximum concentration (Cmax ) in the fed state was lower than in the fasted state (geometric means, 14.1 and 18.1 ng/mL). The geometric mean ratio (90% confidence interval) (fed/fasted states) for Cmax was 77.5% (72.9-82.4%), indicating a food effect on Cmax . There was no difference in tivozanib area under the curve to infinity (AUC0-∞ ) between states (geometric means, 2,377 and 2,198 ng h/mL). Geometric mean ratios also indicated no food effect on tivozanib AUC0-∞ . Other PK parameters were similar between states. The most commonly reported adverse events affected the gastrointestinal system and were mild in intensity. There were no clinically significant changes in other safety measures. In conclusion, food does not have an impact on the AUC0-∞ of tivozanib but does decrease Cmax approximately 23%, suggesting that this agent can be dosed with or without food.

A Phase I cardiac safety and pharmacokinetic study of tivozanib hydrochloride in patients with advanced solid tumors.

Tivozanib hydrochloride (tivozanib) is a potent, selective tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors, with a long half-life. Tivozanib's effects on the QTc interval in patients with advanced solid tumors were assessed. Patients received 1.5 mg of tivozanib orally, once daily, for 21 days. Safety evaluations, serial blood samples for pharmacokinetic measurements, and time-matched, triplicate, 12-lead electrocardiograms (ECG) were collected. Fifty patients were evaluable. The maximum change in QTcF was 9.3 milliseconds (90% confidence interval [CI] 5-13.6), occurring 2.5 hours after dosing on Day 21. The central tendency change across all time points was +2.2 milliseconds. The slope of the exposure-ΔQTcF relationship was 0.08464 ms/ng/mL, with a predicted QTcF change of 8.27 milliseconds at the average tivozanib Tmax of 118.1 ng/mL (upper CI 12.6 milliseconds). There were no QTcF values >500 milliseconds or significant changes from baseline observed in heart rate, PR interval, and QRS complex. These data, evaluated along with other tivozanib preclinical and clinical study results, suggest that administration of 1.5 mg tivozanib for 21 days has a minimal effect on cardiac repolarization or ECG morphology in oncology subjects.

Absorption, Metabolism, and Excretion of [(14) C]-Tivozanib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Healthy Male Participants: A Phase I, Open-Label, Mass-Balance Study.

OBJECTIVE: To evaluate the absorption, metabolism, and excretion of tivozanib, a new investigational drug for renal cell carcinoma and solid malignancies. METHODS: Eight healthy male participants received a single 1.5-mg (˜160 µCi) dose of oral [(14) C]-tivozanib. Whole blood, serum, urine, and feces were evaluated up to 28 days postdose for pharmacokinetics, radioanalysis, and metabolites. Adverse events were recorded throughout the study. RESULTS: [(14) C]-tivozanib concentration peaked at 10.9 ± 5.84 hours. The mean serum half-life for [(14) C]-tivozanib was 89.3 ± 23.5 hours. The maximum concentration and area under the curve for [(14) C]-tivozanib were 12.1 ± 5.67 ng/mL and 1084 ± 417.0 ng·h/mL, respectively. Mean recovery of total radioactivity was 91.0% ± 11.0%; 79.3% ± 8.82% of the radioactivity was recovered in feces both as unchanged tivozanib and metabolites. In the urine, 11.8% ± 4.59% was recovered only as metabolites. No unchanged tivozanib was found in the urine. CONCLUSION: Tivozanib had a long half-life with no major circulating metabolite, was well tolerated as a single dose, and was primarily eliminated via feces with no unchanged tivozanib found in urine. These pharmacokinetic data of [(14) C]-tivozanib are consistent with previous studies of unlabeled tivozanib.