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Alison H Harrill - One of the best experts on this subject based on the ideXlab platform.
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nitrosative stress and lipid homeostasis as a mechanism for Zileuton hepatotoxicity and resistance in genetically sensitive mice
Toxicological Sciences, 2020Co-Authors: Lascelles E Lyncook, Daniel M Gatti, Natalie Bell, Philip R Mayeux, Laura P James, William Mattes, Gary J Larson, Alison H HarrillAbstract:Zileuton is an orally active inhibitor of leukotriene synthesis for maintenance treatment of asthma, for which clinical usage has been associated with idiosyncratic liver injury. Mechanistic understanding of Zileuton toxicity is hampered by the rarity of the cases and lack of an animal model. A promising model for mechanistic study of rare liver injury is the Diversity Outbred (J:DO) mouse population, with genetic variation similar to that found in humans. In this study, female DO mice were administered Zileuton or vehicle i.g. daily for seven days. Serum liver enzymes were elevated in the Zileuton group, with marked interindividual variability in response. Zileuton treatment-induced findings in susceptible DO mice included microvesicular fatty change, hepatocellular mitosis, and hepatocellular necrosis. Inducible nitric oxide synthase (iNOS) and nitrotyrosine abundance were increased in livers of animals with necrosis and those with fatty change, implicating nitrosative stress as a possible injury mechanism. Conversely, DO mice lacking adverse liver pathology following Zileuton exposure experienced decreased hepatic concentrations of resistin and increased concentrations of insulin and leptin, providing potential clues into mechanisms of toxicity resistance. Transcriptome pathway analysis highlighted mitochondrial dysfunction and altered fatty acid oxidation as key molecular perturbations associated with Zileuton exposure, and suggested that interindividual differences in cytochrome P450 metabolism, glutathione-mediated detoxification, and FXR signaling may contribute to Zileuton-induced liver injury. Taken together, DO mice provided a platform for investigating mechanisms of toxicity and resistance in context of Zileuton-induced liver injury which may lead to targeted therapeutic interventions.
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identification of pharmacogenetic risk factors for Zileuton induced liver injury using diversity outbred mice
The FASEB Journal, 2017Co-Authors: Alison H Harrill, Lascelles E Lyncook, Daniel M Gatti, Gary A ChurchillAbstract:Zileuton is an orally active inhibitor of leukotriene synthesis that is currently used for the maintenance treatment of asthma, although there has been interest in expanding its indications to other inflammatory diseases involving leukotrienes, such as rheumatoid arthritis and inflammatory bowel disease. A limitation for expanding clinical usage is an association with rare (idiosyncratic), but serious liver injury. In this study, we hypothesized that genetic sequence variants could be identified that influence risk of Zileuton-induced hepatotoxicity. Diversity Outbred (DO) mice were used as a surrogate for the human population because they harbor a high degree of genetic diversity and this diversity is well-randomized throughout the genome, providing an ideal platform for complex trait analysis. In this study, female DO mice were administered Zileuton (300 mg/kg, N=400) or vehicle (N=50) and dosed daily for seven days (i.g.). Serum alanine aminotransferase (ALT) was significantly elevated in the Zileuton ...
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idiosyncratic drug induced liver injury potential of Zileuton is detected in diversity outbred mice
The FASEB Journal, 2015Co-Authors: Alison H Harrill, Lascelles E Lyncook, Daniel M Gatti, Gary A ChurchillAbstract:Zileuton is an orally active inhibitor of 5-lipoxygenase used clinically for maintenance treatment of asthma. While also a promising candidate for other inflammatory diseases involving leukotrienes, such as rheumatoid arthritis and inflammatory bowel disease, enthusiasm for expanding its indications is tempered by rare instances of associated drug-induced liver injury (DILI). Mechanistic understanding of Zileuton DILI is hampered by the rarity of the cases and lack of an animal model. A promising model for rare liver injury is the Diversity Outbred (DO) mouse population, which contains genetic variation that is similar to that found in humans. We hypothesized that Zileuton DILI could be mediated by rare genetic alleles that are harbored by sensitive patients and thus used the DO mice as a surrogate model for clinical populations. Female DO mice (N=50/group) were orally administered Zileuton (300 mg/kg) or vehicle for seven days. Significant elevations in alanine aminotransferase (ALT) were elicited by zil...
Weizhong Yang - One of the best experts on this subject based on the ideXlab platform.
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5 lox inhibitor Zileuton reduces inflammatory reaction and ischemic brain damage through the activation of pi3k akt signaling pathway
Neurochemical Research, 2016Co-Authors: Xiankun Tu, Chunhua Wang, Chunmei Chen, Huabin Zhang, Risheng Liang, Weizhong YangAbstract:Previous studies from our laboratories showed that an anti-inflammatory drug, 5-lipoxygenase inhibitor Zileuton, attenuates ischemic brain damage via inhibiting inflammatory reaction. However, it was elusive whether Zileuton attenuates inflammatory reaction and ischemic brain damage through the modulation of PI3K/Akt signaling pathway. In the present study, we, for the first time, investigated whether PI3K/Akt pathway was involved in Zileuton’s anti-inflammatory and neuroprotective properties against brain damage following experimental ischemic stroke. Adult male Sprague–Dawley rats underwent middle cerebral artery occlusion (MCAO), then received treatment with Zileuton or vehicle after the onset of ischemia. LY294002 was injected intracerebroventricularly to inhibit the activation of PI3K/Akt signaling pathway selectively. Neurological deficit scores, cerebral infarct volume, morphological characteristic and cerebral water content were assessed 24 h after cerebral ischemia. The enzymatic activity of myeloperoxidase (MPO) was measured 24 h after cerebral ischemia. Expression of p-Akt, t-Akt and COX-2 in ischemic brain were determined by western blot. NF-κB p65 immuno-positive cells in ischemic brain were detected 24 h after cerebral ischemia. The content of TNF-α in blood was examined by ELISA. 5-LOX inhibitor Zileuton significantly reduces neurological deficit scores, cerebral infarct volume, cerebral water content, ischemic neuronal injury and the enzymatic activity of MPO, all of which were abolished by LY294002 administration. Zileuton significantly up-regulates the expression of p-Akt, which was inhibited by LY294002 administration. Zileuton significantly down-regulates the over-expression of NF-κB p65 and COX-2, and attenuates the release of TNF-α, all of which were disminished by LY294002 administration. These results suggest that Zileuton attenuates ischemic brain damage by inhibiting inflammatory reaction through the activation of PI3K/Akt signaling pathway.
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5 lipoxygenase inhibitor Zileuton inhibits neuronal apoptosis following focal cerebral ischemia
Inflammation, 2013Co-Authors: Weizhong Yang, Xiankun Tu, Chunhua Wang, Chenmei Chen, Yan ChenAbstract:Previous studies from our laboratory demonstrated that Zileuton, a selective 5-lipoxygenase (5-LOX) inhibitor, attenuates ischemic brain damage in rats of focal cerebral ischemia. Enormous evidences showed that inflammatory reaction and neuronal apoptosis are the two important pathophysiological events in ischemia-induced brain damage. Our previous studies demonstrate that Zileuton attenuates ischemic brain damage via inhibiting inflammatory reaction. The present study was performed to explore whether 5-LOX inhibitor Zileuton attenuates neuronal apoptosis following focal cerebral ischemia and further investigate the potent mechanisms underlying its neuroprotection. Adult male Sprague–Dawley rats underwent permanent middle cerebral artery occlusion (MCAO) for 72 h, then received intragastric gavage with Zileuton or vehicle as a bolus after the onset of MCAO. Neurological deficit scores, cerebral infarct volume, and neuronal damage were measured 72 h after MCAO. TUNEL staining was performed to measure the extent of neuronal apoptosis. Reverse transcription-polymerase chain reaction was performed to determine the expression of caspase-1 mRNA. Western blot was performed to determine the expression of procaspase-3 and cleaved caspase-3 in rat brain. Neurological deficit scores, infarct volume, and neuronal damage were significantly attenuated by administration of Zileuton. MCAO caused the elevation of neuronal apoptosis, which was significantly inhibited by the administration of Zileuton. MCAO caused the over-expression of caspase-1 and cleaved caspase-3, both of which were significantly inhibited by the administration of Zileuton. Expression of procaspase-3 was reduced after MCAO, which was significantly up-regulated by administration of Zileuton. Our studies suggested that 5-LOX inhibitor Zileuton reduces MCAO-induced brain damage and neuronal apoptosis, which might be associated with the inhibition of caspase-1 and the regulation of caspase-3.
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Zileuton reduces inflammatory reaction and brain damage following permanent cerebral ischemia in rats
Inflammation, 2010Co-Authors: Xiankun Tu, Weizhong Yang, Chunhua Wang, Chunmei Chen, Yongliang Zhang, Yikun YangAbstract:5-Lipoxygenase inhibitor Zileuton has been demonstrated to attenuate ischemic brain damage in rats of permanent focal cerebral ischemia in previous work. To further investigate the mechanism underlying Zileuton's neuroprotection, adult male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (MCAO), then received treatment with Zileuton or vehicle after the onset of ischemia. Neurological deficit, cerebral infarction, and morphological characteristic were measured 6 and 24 h after MCAO. The enzymatic activity of myeloperoxidase (MPO) was assessed 6 and 24 h after MCAO and the lipid peroxidation levels were evaluated by malondialdehyde assay. Expression of nuclear factor-kappa B (NF-κB) p65 in rat brain was detected by immunohistochemistry and Western blot. Expression of inducible nitric oxide synthase (iNOS) in rat brain was determined by RT-PCR and Western blot. Nitric oxide production in rat brain was also measured 24 h after MCAO. The concentration of TNF-α and IL-1β in serum were detected by ELISA. Zileuton significantly reduced neurological deficit scores, cerebral infarct volume, MPO activity, and the lipid peroxidation levels. It also inhibited the expression of NF-κB and decreased the expression and activity of iNOS in rat brain. In addition, Zileuton attenuated the release of TNF-α and IL-1β in serum. Our results suggest that Zileuton reduces inflammatory reaction and brain damage in a rat model of permanent focal cerebral ischemia. The neuroprotective effect of Zileuton in cerebral ischemia might be associated with the inhibition of inflammatory reaction.
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5 lipoxygenase inhibitor Zileuton attenuates ischemic brain damage involvement of matrix metalloproteinase 9
Neurological Research, 2009Co-Authors: Xiankun Tu, Weizhong Yang, Chunmei Chen, Chunhua WangAbstract:Abstract Objectives: Cerebral ischemia causes an increased expression and activation of 5-lipoxygenase (5-LOX) and matrix metalloproteinase 9 (MMP-9). Recent works demonstrated that the selective 5-LOX inhibitor Zileuton down-regulates MMP-9 expression in vascular diseases and cancer. In the present work, we first studied the neuroprotective effect of Zileuton on focal cerebral ischemia in rats and further investigated the effect of Zileuton on the expression of 5-LOX and MMP-9 in ischemic brain. Methods: Adult Sprague–Dawley rats underwent permanent middle cerebral artery occlusion (pMCAO). The rats then received treatment with Zileuton 5, 10 or 50 mg/kg or vehicle. Cerebral water content and infarct volume were measured 24 hours after pMCAO. Expression of 5-LOX messenger RNA (mRNA) and MMP-9 mRNA were determined by reverse transcription polymerase chain reaction. The levels of the proform and the active form of MMP-9 were detected by gelatin zymography. Results: Oral treatment of Zileuton at 10 or 50 mg...
Xiankun Tu - One of the best experts on this subject based on the ideXlab platform.
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5 lox inhibitor Zileuton reduces inflammatory reaction and ischemic brain damage through the activation of pi3k akt signaling pathway
Neurochemical Research, 2016Co-Authors: Xiankun Tu, Chunhua Wang, Chunmei Chen, Huabin Zhang, Risheng Liang, Weizhong YangAbstract:Previous studies from our laboratories showed that an anti-inflammatory drug, 5-lipoxygenase inhibitor Zileuton, attenuates ischemic brain damage via inhibiting inflammatory reaction. However, it was elusive whether Zileuton attenuates inflammatory reaction and ischemic brain damage through the modulation of PI3K/Akt signaling pathway. In the present study, we, for the first time, investigated whether PI3K/Akt pathway was involved in Zileuton’s anti-inflammatory and neuroprotective properties against brain damage following experimental ischemic stroke. Adult male Sprague–Dawley rats underwent middle cerebral artery occlusion (MCAO), then received treatment with Zileuton or vehicle after the onset of ischemia. LY294002 was injected intracerebroventricularly to inhibit the activation of PI3K/Akt signaling pathway selectively. Neurological deficit scores, cerebral infarct volume, morphological characteristic and cerebral water content were assessed 24 h after cerebral ischemia. The enzymatic activity of myeloperoxidase (MPO) was measured 24 h after cerebral ischemia. Expression of p-Akt, t-Akt and COX-2 in ischemic brain were determined by western blot. NF-κB p65 immuno-positive cells in ischemic brain were detected 24 h after cerebral ischemia. The content of TNF-α in blood was examined by ELISA. 5-LOX inhibitor Zileuton significantly reduces neurological deficit scores, cerebral infarct volume, cerebral water content, ischemic neuronal injury and the enzymatic activity of MPO, all of which were abolished by LY294002 administration. Zileuton significantly up-regulates the expression of p-Akt, which was inhibited by LY294002 administration. Zileuton significantly down-regulates the over-expression of NF-κB p65 and COX-2, and attenuates the release of TNF-α, all of which were disminished by LY294002 administration. These results suggest that Zileuton attenuates ischemic brain damage by inhibiting inflammatory reaction through the activation of PI3K/Akt signaling pathway.
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5 lipoxygenase inhibitor Zileuton inhibits neuronal apoptosis following focal cerebral ischemia
Inflammation, 2013Co-Authors: Weizhong Yang, Xiankun Tu, Chunhua Wang, Chenmei Chen, Yan ChenAbstract:Previous studies from our laboratory demonstrated that Zileuton, a selective 5-lipoxygenase (5-LOX) inhibitor, attenuates ischemic brain damage in rats of focal cerebral ischemia. Enormous evidences showed that inflammatory reaction and neuronal apoptosis are the two important pathophysiological events in ischemia-induced brain damage. Our previous studies demonstrate that Zileuton attenuates ischemic brain damage via inhibiting inflammatory reaction. The present study was performed to explore whether 5-LOX inhibitor Zileuton attenuates neuronal apoptosis following focal cerebral ischemia and further investigate the potent mechanisms underlying its neuroprotection. Adult male Sprague–Dawley rats underwent permanent middle cerebral artery occlusion (MCAO) for 72 h, then received intragastric gavage with Zileuton or vehicle as a bolus after the onset of MCAO. Neurological deficit scores, cerebral infarct volume, and neuronal damage were measured 72 h after MCAO. TUNEL staining was performed to measure the extent of neuronal apoptosis. Reverse transcription-polymerase chain reaction was performed to determine the expression of caspase-1 mRNA. Western blot was performed to determine the expression of procaspase-3 and cleaved caspase-3 in rat brain. Neurological deficit scores, infarct volume, and neuronal damage were significantly attenuated by administration of Zileuton. MCAO caused the elevation of neuronal apoptosis, which was significantly inhibited by the administration of Zileuton. MCAO caused the over-expression of caspase-1 and cleaved caspase-3, both of which were significantly inhibited by the administration of Zileuton. Expression of procaspase-3 was reduced after MCAO, which was significantly up-regulated by administration of Zileuton. Our studies suggested that 5-LOX inhibitor Zileuton reduces MCAO-induced brain damage and neuronal apoptosis, which might be associated with the inhibition of caspase-1 and the regulation of caspase-3.
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Zileuton reduces inflammatory reaction and brain damage following permanent cerebral ischemia in rats
Inflammation, 2010Co-Authors: Xiankun Tu, Weizhong Yang, Chunhua Wang, Chunmei Chen, Yongliang Zhang, Yikun YangAbstract:5-Lipoxygenase inhibitor Zileuton has been demonstrated to attenuate ischemic brain damage in rats of permanent focal cerebral ischemia in previous work. To further investigate the mechanism underlying Zileuton's neuroprotection, adult male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (MCAO), then received treatment with Zileuton or vehicle after the onset of ischemia. Neurological deficit, cerebral infarction, and morphological characteristic were measured 6 and 24 h after MCAO. The enzymatic activity of myeloperoxidase (MPO) was assessed 6 and 24 h after MCAO and the lipid peroxidation levels were evaluated by malondialdehyde assay. Expression of nuclear factor-kappa B (NF-κB) p65 in rat brain was detected by immunohistochemistry and Western blot. Expression of inducible nitric oxide synthase (iNOS) in rat brain was determined by RT-PCR and Western blot. Nitric oxide production in rat brain was also measured 24 h after MCAO. The concentration of TNF-α and IL-1β in serum were detected by ELISA. Zileuton significantly reduced neurological deficit scores, cerebral infarct volume, MPO activity, and the lipid peroxidation levels. It also inhibited the expression of NF-κB and decreased the expression and activity of iNOS in rat brain. In addition, Zileuton attenuated the release of TNF-α and IL-1β in serum. Our results suggest that Zileuton reduces inflammatory reaction and brain damage in a rat model of permanent focal cerebral ischemia. The neuroprotective effect of Zileuton in cerebral ischemia might be associated with the inhibition of inflammatory reaction.
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5 lipoxygenase inhibitor Zileuton attenuates ischemic brain damage involvement of matrix metalloproteinase 9
Neurological Research, 2009Co-Authors: Xiankun Tu, Weizhong Yang, Chunmei Chen, Chunhua WangAbstract:Abstract Objectives: Cerebral ischemia causes an increased expression and activation of 5-lipoxygenase (5-LOX) and matrix metalloproteinase 9 (MMP-9). Recent works demonstrated that the selective 5-LOX inhibitor Zileuton down-regulates MMP-9 expression in vascular diseases and cancer. In the present work, we first studied the neuroprotective effect of Zileuton on focal cerebral ischemia in rats and further investigated the effect of Zileuton on the expression of 5-LOX and MMP-9 in ischemic brain. Methods: Adult Sprague–Dawley rats underwent permanent middle cerebral artery occlusion (pMCAO). The rats then received treatment with Zileuton 5, 10 or 50 mg/kg or vehicle. Cerebral water content and infarct volume were measured 24 hours after pMCAO. Expression of 5-LOX messenger RNA (mRNA) and MMP-9 mRNA were determined by reverse transcription polymerase chain reaction. The levels of the proform and the active form of MMP-9 were detected by gelatin zymography. Results: Oral treatment of Zileuton at 10 or 50 mg...
Louise M Dube - One of the best experts on this subject based on the ideXlab platform.
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evaluation of the diurnal variation in the pharmacokinetics of Zileuton in healthy volunteers
The Journal of Clinical Pharmacology, 1997Co-Authors: Walid M Awni, Charles Locke, Louise M Dube, John H CavanaughAbstract:The diurnal variation in the pharmacokinetic parameters of Zileuton were evaluated in 12 healthy male volunteers in a three-period study. Periods I and II constituted a balanced, randomized, crossover study in which a participant received a single dose of 600-mg Zileuton either at 7 AM or 11 PM. In period III all participants received 600-mg doses four times daily for 5 days. The differences between the pharmacokinetics of single doses of Zileuton administered at 7 AM and at 11 PM were not statistically signijicant. Plasma concentration - time profiles of Zileuton during the four daily dose intervals at steady state were also similar. Values for the pharmacokinetic parameters of Zileuton after multiple doses were similar to those after single doses, with a minimal accumulation of the drug after multiple doses. Overall, there was little or no diurnal variation in the pharmacokinetic parameters of Zileuton after single and multiple doses.
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the influence of multiple oral doses of Zileuton on the steady state pharmacokinetics of sulfasalazine and its metabolites sulfapyridine and n acetylsulfapyridine
Clinical Pharmacokinectics, 1995Co-Authors: Walid M Awni, Rene A Braeckman, Charles Locke, Louise M Dube, Richard G GrannemanAbstract:The effects of Zileuton (Abbott-64077) on the pharmacokinetics of sulfasalazine (SASP) and its metabolites, sulfapyridine (SP) and N-acetylsulfapyridine (ASP), were studied in a randomised double-blind placebocontrolled study enrolling 14 healthy male volunteers. All subjects received SASP 1g every 12 hours for 8 days and Zileuton 800mg or placebo administered twice daily from day 4 to day 8 inclusive. Coadministration of Zileuton did not significantly affect the area under the plasma concentration-time curve, the maximum (Cmax) or minimum (Cmin) plasma concentration and the time to Cmax of SASP, SP or ASP. Likewise, Zileuton did not modify the terminal elimination half-life of SASP. It is concluded that coadministration of Zileuton 1.6 g/day has no significant effects on the pharmacokinetics of SASP 2 g/day or its metabolites, SP and ASP.
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The Pharmacokinetics of Single Oral Doses of Zileuton 200 to 800mg, its Enantiomers, and its Metabolites, in Normal Healthy Volunteers
Clinical Pharmacokinetics, 1995Co-Authors: Shekman L Wong, Charles S Locke, John H Cavanaugh, Walid M Awni, Tawakol El-shourbagy, Louise M DubeAbstract:The pharmacokinetics of single oral doses of Zileuton 200 to 800mg, its R(+) and S(−) enantiomers, and its Af-dehydroxylated and glucuronide metabolites have been investigated in a randomised study in 16 normal male healthy volunteers. Zileuton was 93.4% bound to plasma proteins. The overall dispositional pharmacokinetics of Zileuton racemate appeared to be linear. The mean dosenormalised area under the concentration-time curve from zero to infinity (AUC_0-∞) remained constant, while the mean dose-normalised peak plasma concentration (C_max) decreased with the increase in dose, possibly because of dissolution rate-limited absorption at the higher doses. The R(+) and S(−) enantiomers of Zileuton may have similar absorption profiles, although the apparent total plasma clearance of the S(−) enantiomer was 49 to 76% higher than the corresponding values for the R(+) enantiomer. The AUC_-∞ of each enantiomer increased proportionately with dose. The pharmacokinetics of the N -dehydroxylated metabolite of Zileuton were highly variable, with a more than dose-proportional increase in the mean dosenormalised C_max and area under the concentration-time curve from zero to 24 hours. The elimination of the glucuronide metabolites of the R(+) and S(−) enantiomers of Zileuton was formation rate-limited. The mean percentage of the administered Zileuton dose recovered in urine as glucuronide metabolites ranged from 73.1 to 76.5% and showed no dose-related differences. The renal clearances of the glucuronide metabolites of Zileuton exceeded the normal glomerular filtration rate, suggesting that these metabolites may be excreted through renal tubular secretion in addition to filtration.
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pharmacokinetics and pharmacodynamics of Zileuton after oral administration of single and multiple dose regimens of Zileuton 600mg in healthy volunteers
Clinical Pharmacokinectics, 1995Co-Authors: Walid M Awni, Rene A Braeckman, Richard G Granneman, Galen Witt, Louise M DubeAbstract:The pharmacokinetics and pharmacodynamics of Zileuton were determined after oral administration of single dose (600mg) and multiple dose regimens [600mg every 8 hours (q8h regimen) and 600mg every 6 hours (q6h regimen)] in 12 healthy male subjects aged 18 to 50 years. Steady-state peak plasma concentration (Cmax), time to Cmax, apparent total plasma clearance, and apparent terminal phase volume of distribution values after the q8h and q6h regimens were 3.07 ± 1.13 and 4.37 ± 1.02 mg/L, 1.5 ±0.9 and 1.5 ±0.9 hours, 793 ± 233 and 579 ± 162 ml/min (47.6 and 34.7 L/h), and 179 ± 126 and 115 ± 29L, respectively (mean ± SD). Trough Zileuton plasma concentrations (Cmin) immeiately before the morning dose were higher than Cmin immediately before the afternoon dose, suggesting a diurnal variation in the pharmacokinetics of Zileuton. Accumulation of Zileuton occurred with more frequent dose administration, although there was no unexpected accumulation of the parent drug or the N-dehydroxyZileuton metabolite. The q6h regimen of Zileuton 600mg was superior to the q8h regimen in maintaining trough plasma concentrations of Zileuton above 1.5 mg/L, corresponding to approximately 70 to 80% inhibition of leukotriene B4 biosynthesis.
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assessment of the pharmacokinetic interaction between Zileuton and digoxin in humans
Clinical Pharmacokinectics, 1995Co-Authors: Walid M Awni, Richard G Granneman, John H Cavanaugh, Ziad Hussein, Louise M DubeAbstract:The effects of coadministration of Zileuton on the pharmacokinetic profile of digoxin were investigated in a double-blind placebo-controlled crossover study in 12 healthy male volunteers. During each study phase, the subjects received Zileuton 600mg every 6 hours (regimen A) or placebo (regimen B) for 13 days. In addition, all subjects received concomitant digoxin 0.25 mg/day on study days 1 to 11 during both study phases. The study results provide no evidence of any significant overall effect of Zileuton on digoxin plasma concentration-time profiles. Although the mean time to reach the maximum plasma concentration for digoxin was significantly shorter after concomitant administration of digoxin and Zileuton than after concomitant administration of digoxin and placebo (0.95 vs 1.43 hours), there were no significant differences between the 2 regimens in the values for maximum plasma concentration, area under the plasma concentration-time curve from 0 to 24 hours, elimination half-life, oral clearance, and apparent volume of distribution associated with the terminal phase. Therefore, it is concluded that digoxin and Zileuton may be coadministered without risk of clinically relevant effects on the pharmacokinetic profile of digoxin.
Walid M Awni - One of the best experts on this subject based on the ideXlab platform.
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evaluation of the diurnal variation in the pharmacokinetics of Zileuton in healthy volunteers
The Journal of Clinical Pharmacology, 1997Co-Authors: Walid M Awni, Charles Locke, Louise M Dube, John H CavanaughAbstract:The diurnal variation in the pharmacokinetic parameters of Zileuton were evaluated in 12 healthy male volunteers in a three-period study. Periods I and II constituted a balanced, randomized, crossover study in which a participant received a single dose of 600-mg Zileuton either at 7 AM or 11 PM. In period III all participants received 600-mg doses four times daily for 5 days. The differences between the pharmacokinetics of single doses of Zileuton administered at 7 AM and at 11 PM were not statistically signijicant. Plasma concentration - time profiles of Zileuton during the four daily dose intervals at steady state were also similar. Values for the pharmacokinetic parameters of Zileuton after multiple doses were similar to those after single doses, with a minimal accumulation of the drug after multiple doses. Overall, there was little or no diurnal variation in the pharmacokinetic parameters of Zileuton after single and multiple doses.
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pharmacokinetics of Zileuton and its metabolites in patients with renal impairment
The Journal of Clinical Pharmacology, 1997Co-Authors: Walid M Awni, Shekman L Wong, Karen Patterson, Robert S Hansen, Joseph M Machinist, Jeff Drajesk, William F Keane, C E HalstensonAbstract:The pharmacokinetics of Zileuton and its conjugated metabolites were evaluated in patients with chronic renal impairment. Five healthy volunteers (creatinine clearance >90 mL/min), five patients with renal failure requiring hemodialysis, six with mild (creatinine clearance, 60-90 mL/min), eight with moderate (creatinine clearance, 30-59 mL/min), and six with severe (creatinine clearance <30 mL/min) renal impairment participated in the study. Zileuton was well tolerated by all participants including those with severe renal impairment and those receiving hemodialysis. The pharmacokinetics of Zileuton were similar in healthy volunteers; in patients with mild, moderate and severe renal impairment; and in patients with renal failure requiring hemodialysis. The mean metabolite/parent-area ratios for the pharmacologically inactive Zileuton glucuronides progressively increased with the decline in renal function. A very small percentage of the administered Zileuton dose (<0.5%) was removed by hemodialysis. Therefore, adjustment in the dose regimen of Zileuton does not appear to be necessary for patients with various degrees of renal impairment and patients with renal failure requiring hemodialysis.
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the influence of multiple oral doses of Zileuton on the steady state pharmacokinetics of sulfasalazine and its metabolites sulfapyridine and n acetylsulfapyridine
Clinical Pharmacokinectics, 1995Co-Authors: Walid M Awni, Rene A Braeckman, Charles Locke, Louise M Dube, Richard G GrannemanAbstract:The effects of Zileuton (Abbott-64077) on the pharmacokinetics of sulfasalazine (SASP) and its metabolites, sulfapyridine (SP) and N-acetylsulfapyridine (ASP), were studied in a randomised double-blind placebocontrolled study enrolling 14 healthy male volunteers. All subjects received SASP 1g every 12 hours for 8 days and Zileuton 800mg or placebo administered twice daily from day 4 to day 8 inclusive. Coadministration of Zileuton did not significantly affect the area under the plasma concentration-time curve, the maximum (Cmax) or minimum (Cmin) plasma concentration and the time to Cmax of SASP, SP or ASP. Likewise, Zileuton did not modify the terminal elimination half-life of SASP. It is concluded that coadministration of Zileuton 1.6 g/day has no significant effects on the pharmacokinetics of SASP 2 g/day or its metabolites, SP and ASP.
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The Pharmacokinetics of Single Oral Doses of Zileuton 200 to 800mg, its Enantiomers, and its Metabolites, in Normal Healthy Volunteers
Clinical Pharmacokinetics, 1995Co-Authors: Shekman L Wong, Charles S Locke, John H Cavanaugh, Walid M Awni, Tawakol El-shourbagy, Louise M DubeAbstract:The pharmacokinetics of single oral doses of Zileuton 200 to 800mg, its R(+) and S(−) enantiomers, and its Af-dehydroxylated and glucuronide metabolites have been investigated in a randomised study in 16 normal male healthy volunteers. Zileuton was 93.4% bound to plasma proteins. The overall dispositional pharmacokinetics of Zileuton racemate appeared to be linear. The mean dosenormalised area under the concentration-time curve from zero to infinity (AUC_0-∞) remained constant, while the mean dose-normalised peak plasma concentration (C_max) decreased with the increase in dose, possibly because of dissolution rate-limited absorption at the higher doses. The R(+) and S(−) enantiomers of Zileuton may have similar absorption profiles, although the apparent total plasma clearance of the S(−) enantiomer was 49 to 76% higher than the corresponding values for the R(+) enantiomer. The AUC_-∞ of each enantiomer increased proportionately with dose. The pharmacokinetics of the N -dehydroxylated metabolite of Zileuton were highly variable, with a more than dose-proportional increase in the mean dosenormalised C_max and area under the concentration-time curve from zero to 24 hours. The elimination of the glucuronide metabolites of the R(+) and S(−) enantiomers of Zileuton was formation rate-limited. The mean percentage of the administered Zileuton dose recovered in urine as glucuronide metabolites ranged from 73.1 to 76.5% and showed no dose-related differences. The renal clearances of the glucuronide metabolites of Zileuton exceeded the normal glomerular filtration rate, suggesting that these metabolites may be excreted through renal tubular secretion in addition to filtration.
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pharmacokinetics and pharmacodynamics of Zileuton after oral administration of single and multiple dose regimens of Zileuton 600mg in healthy volunteers
Clinical Pharmacokinectics, 1995Co-Authors: Walid M Awni, Rene A Braeckman, Richard G Granneman, Galen Witt, Louise M DubeAbstract:The pharmacokinetics and pharmacodynamics of Zileuton were determined after oral administration of single dose (600mg) and multiple dose regimens [600mg every 8 hours (q8h regimen) and 600mg every 6 hours (q6h regimen)] in 12 healthy male subjects aged 18 to 50 years. Steady-state peak plasma concentration (Cmax), time to Cmax, apparent total plasma clearance, and apparent terminal phase volume of distribution values after the q8h and q6h regimens were 3.07 ± 1.13 and 4.37 ± 1.02 mg/L, 1.5 ±0.9 and 1.5 ±0.9 hours, 793 ± 233 and 579 ± 162 ml/min (47.6 and 34.7 L/h), and 179 ± 126 and 115 ± 29L, respectively (mean ± SD). Trough Zileuton plasma concentrations (Cmin) immeiately before the morning dose were higher than Cmin immediately before the afternoon dose, suggesting a diurnal variation in the pharmacokinetics of Zileuton. Accumulation of Zileuton occurred with more frequent dose administration, although there was no unexpected accumulation of the parent drug or the N-dehydroxyZileuton metabolite. The q6h regimen of Zileuton 600mg was superior to the q8h regimen in maintaining trough plasma concentrations of Zileuton above 1.5 mg/L, corresponding to approximately 70 to 80% inhibition of leukotriene B4 biosynthesis.
