The Experts below are selected from a list of 117 Experts worldwide ranked by ideXlab platform
Timothy L Macdonald - One of the best experts on this subject based on the ideXlab platform.
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the chemistry toxicology and identification in rat and human urine of 4 hydroxy 5 phenyl 1 3 oxazaperhydroin 2 one a reactive metabolite in felbamate bioactivation
2001Co-Authors: Christine M Dieckhaus, Webster L Santos, Duane R Sofia, Timothy L MacdonaldAbstract:4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one has been proposed to be a reactive metabolite of the anti-epileptic drug felbamate [Thompson et al. (1996) Chem. Res. Toxicol. 9, 1225−1229]. 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one exists in equilibrium with 3-oxo-2-phenylpropyl aminooate, which is known to eliminate to generate 2-phenylpropenal. Thus, this species is postulated to be a latent form of the ultimate reactive metabolite, 2-phenylpropenal. The chemistry of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is proposed to parallel that of 4-hydroxycyclophosphamide, the bioactivated form of cyclophosphamide that undergoes ring-opening to Aldophosphamide and subsequent elimination to afford 2-propenal (acrolein). The work presented here reports the chemical synthesis of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one and demonstrates that under buffered conditions it exists in equilibrium with 3-oxo-2-phenylpropyl aminooate. The rate-limiting step in the decomposition of 4-hydroxy-5-phenyl-1,3-oxazaperhy...
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The Chemistry, Toxicology, and Identification in Rat and Human Urine of 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one: A Reactive Metabolite in Felbamate Bioactivation
2000Co-Authors: Christine M Dieckhaus, Webster L Santos, Duane R Sofia, Timothy L MacdonaldAbstract:4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one has been proposed to be a reactive metabolite of the anti-epileptic drug felbamate [Thompson et al. (1996) Chem. Res. Toxicol. 9, 1225-1229]. 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one exists in equilibrium with 3-oxo-2-phenylpropyl aminooate, which is known to eliminate to generate 2-phenylpropenal. Thus, this species is postulated to be a latent form of the ultimate reactive metabolite, 2-phenylpro-penal. The chemistry of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is proposed to parallel that of 4-hydroxycyclophosphamide, the bioactivated form of cyclophosphamide that undergoes ring-opening to Aldophosphamide and subsequent elimination to afford 2-propenal (acrolein). The work presented here reports the chemical synthesis of 4-hydroxy-5-phenyl-1,3-oxazaper-hydroin-2-one and demonstrates that under buffered conditions it exists in equilibrium with 3-oxo-2-phenylpropyl aminooate. The rate-limiting step in the decomposition of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is the irreversible â-elimination from 3-oxo-2-phenylpropyl aminooate to 2-phenylpropenal. We have found the half-life of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one to be 4.6 ( 0.4 h under in vitro conditions that mimic the physiological setting. As a consequence of the relatively long half-life of 4-hydroxy-5-phenyl-1,3-oxazaper
Christine M Dieckhaus - One of the best experts on this subject based on the ideXlab platform.
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the chemistry toxicology and identification in rat and human urine of 4 hydroxy 5 phenyl 1 3 oxazaperhydroin 2 one a reactive metabolite in felbamate bioactivation
2001Co-Authors: Christine M Dieckhaus, Webster L Santos, Duane R Sofia, Timothy L MacdonaldAbstract:4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one has been proposed to be a reactive metabolite of the anti-epileptic drug felbamate [Thompson et al. (1996) Chem. Res. Toxicol. 9, 1225−1229]. 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one exists in equilibrium with 3-oxo-2-phenylpropyl aminooate, which is known to eliminate to generate 2-phenylpropenal. Thus, this species is postulated to be a latent form of the ultimate reactive metabolite, 2-phenylpropenal. The chemistry of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is proposed to parallel that of 4-hydroxycyclophosphamide, the bioactivated form of cyclophosphamide that undergoes ring-opening to Aldophosphamide and subsequent elimination to afford 2-propenal (acrolein). The work presented here reports the chemical synthesis of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one and demonstrates that under buffered conditions it exists in equilibrium with 3-oxo-2-phenylpropyl aminooate. The rate-limiting step in the decomposition of 4-hydroxy-5-phenyl-1,3-oxazaperhy...
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The Chemistry, Toxicology, and Identification in Rat and Human Urine of 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one: A Reactive Metabolite in Felbamate Bioactivation
2000Co-Authors: Christine M Dieckhaus, Webster L Santos, Duane R Sofia, Timothy L MacdonaldAbstract:4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one has been proposed to be a reactive metabolite of the anti-epileptic drug felbamate [Thompson et al. (1996) Chem. Res. Toxicol. 9, 1225-1229]. 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one exists in equilibrium with 3-oxo-2-phenylpropyl aminooate, which is known to eliminate to generate 2-phenylpropenal. Thus, this species is postulated to be a latent form of the ultimate reactive metabolite, 2-phenylpro-penal. The chemistry of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is proposed to parallel that of 4-hydroxycyclophosphamide, the bioactivated form of cyclophosphamide that undergoes ring-opening to Aldophosphamide and subsequent elimination to afford 2-propenal (acrolein). The work presented here reports the chemical synthesis of 4-hydroxy-5-phenyl-1,3-oxazaper-hydroin-2-one and demonstrates that under buffered conditions it exists in equilibrium with 3-oxo-2-phenylpropyl aminooate. The rate-limiting step in the decomposition of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is the irreversible â-elimination from 3-oxo-2-phenylpropyl aminooate to 2-phenylpropenal. We have found the half-life of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one to be 4.6 ( 0.4 h under in vitro conditions that mimic the physiological setting. As a consequence of the relatively long half-life of 4-hydroxy-5-phenyl-1,3-oxazaper
Webster L Santos - One of the best experts on this subject based on the ideXlab platform.
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the chemistry toxicology and identification in rat and human urine of 4 hydroxy 5 phenyl 1 3 oxazaperhydroin 2 one a reactive metabolite in felbamate bioactivation
2001Co-Authors: Christine M Dieckhaus, Webster L Santos, Duane R Sofia, Timothy L MacdonaldAbstract:4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one has been proposed to be a reactive metabolite of the anti-epileptic drug felbamate [Thompson et al. (1996) Chem. Res. Toxicol. 9, 1225−1229]. 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one exists in equilibrium with 3-oxo-2-phenylpropyl aminooate, which is known to eliminate to generate 2-phenylpropenal. Thus, this species is postulated to be a latent form of the ultimate reactive metabolite, 2-phenylpropenal. The chemistry of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is proposed to parallel that of 4-hydroxycyclophosphamide, the bioactivated form of cyclophosphamide that undergoes ring-opening to Aldophosphamide and subsequent elimination to afford 2-propenal (acrolein). The work presented here reports the chemical synthesis of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one and demonstrates that under buffered conditions it exists in equilibrium with 3-oxo-2-phenylpropyl aminooate. The rate-limiting step in the decomposition of 4-hydroxy-5-phenyl-1,3-oxazaperhy...
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The Chemistry, Toxicology, and Identification in Rat and Human Urine of 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one: A Reactive Metabolite in Felbamate Bioactivation
2000Co-Authors: Christine M Dieckhaus, Webster L Santos, Duane R Sofia, Timothy L MacdonaldAbstract:4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one has been proposed to be a reactive metabolite of the anti-epileptic drug felbamate [Thompson et al. (1996) Chem. Res. Toxicol. 9, 1225-1229]. 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one exists in equilibrium with 3-oxo-2-phenylpropyl aminooate, which is known to eliminate to generate 2-phenylpropenal. Thus, this species is postulated to be a latent form of the ultimate reactive metabolite, 2-phenylpro-penal. The chemistry of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is proposed to parallel that of 4-hydroxycyclophosphamide, the bioactivated form of cyclophosphamide that undergoes ring-opening to Aldophosphamide and subsequent elimination to afford 2-propenal (acrolein). The work presented here reports the chemical synthesis of 4-hydroxy-5-phenyl-1,3-oxazaper-hydroin-2-one and demonstrates that under buffered conditions it exists in equilibrium with 3-oxo-2-phenylpropyl aminooate. The rate-limiting step in the decomposition of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is the irreversible â-elimination from 3-oxo-2-phenylpropyl aminooate to 2-phenylpropenal. We have found the half-life of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one to be 4.6 ( 0.4 h under in vitro conditions that mimic the physiological setting. As a consequence of the relatively long half-life of 4-hydroxy-5-phenyl-1,3-oxazaper
Duane R Sofia - One of the best experts on this subject based on the ideXlab platform.
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the chemistry toxicology and identification in rat and human urine of 4 hydroxy 5 phenyl 1 3 oxazaperhydroin 2 one a reactive metabolite in felbamate bioactivation
2001Co-Authors: Christine M Dieckhaus, Webster L Santos, Duane R Sofia, Timothy L MacdonaldAbstract:4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one has been proposed to be a reactive metabolite of the anti-epileptic drug felbamate [Thompson et al. (1996) Chem. Res. Toxicol. 9, 1225−1229]. 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one exists in equilibrium with 3-oxo-2-phenylpropyl aminooate, which is known to eliminate to generate 2-phenylpropenal. Thus, this species is postulated to be a latent form of the ultimate reactive metabolite, 2-phenylpropenal. The chemistry of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is proposed to parallel that of 4-hydroxycyclophosphamide, the bioactivated form of cyclophosphamide that undergoes ring-opening to Aldophosphamide and subsequent elimination to afford 2-propenal (acrolein). The work presented here reports the chemical synthesis of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one and demonstrates that under buffered conditions it exists in equilibrium with 3-oxo-2-phenylpropyl aminooate. The rate-limiting step in the decomposition of 4-hydroxy-5-phenyl-1,3-oxazaperhy...
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The Chemistry, Toxicology, and Identification in Rat and Human Urine of 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one: A Reactive Metabolite in Felbamate Bioactivation
2000Co-Authors: Christine M Dieckhaus, Webster L Santos, Duane R Sofia, Timothy L MacdonaldAbstract:4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one has been proposed to be a reactive metabolite of the anti-epileptic drug felbamate [Thompson et al. (1996) Chem. Res. Toxicol. 9, 1225-1229]. 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one exists in equilibrium with 3-oxo-2-phenylpropyl aminooate, which is known to eliminate to generate 2-phenylpropenal. Thus, this species is postulated to be a latent form of the ultimate reactive metabolite, 2-phenylpro-penal. The chemistry of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is proposed to parallel that of 4-hydroxycyclophosphamide, the bioactivated form of cyclophosphamide that undergoes ring-opening to Aldophosphamide and subsequent elimination to afford 2-propenal (acrolein). The work presented here reports the chemical synthesis of 4-hydroxy-5-phenyl-1,3-oxazaper-hydroin-2-one and demonstrates that under buffered conditions it exists in equilibrium with 3-oxo-2-phenylpropyl aminooate. The rate-limiting step in the decomposition of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is the irreversible â-elimination from 3-oxo-2-phenylpropyl aminooate to 2-phenylpropenal. We have found the half-life of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one to be 4.6 ( 0.4 h under in vitro conditions that mimic the physiological setting. As a consequence of the relatively long half-life of 4-hydroxy-5-phenyl-1,3-oxazaper
Louise B Grochow - One of the best experts on this subject based on the ideXlab platform.
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nonlinear pharmacokinetics of cyclophosphamide and 4 hydroxycyclophosphamide Aldophosphamide in patients with metastatic breast cancer receiving high dose chemotherapy followed by autologous bone marrow transplantation
1997Co-Authors: Tian Ling Chen, Lawrence W Anderson, Susan B Kiraly, Kraig C Black, John M Kennedy, Michael O Colvin, Louise B GrochowAbstract:The pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide/Aldophosphamide has been evaluated in 12 patients with metastatic breast cancer undergoing high-dose chemotherapy followed by bone marrow transplantation. Each patient received an initial dose of 4 g/m 2 of cyclophosphamide over 90 min to prime peripheral blood progenitor cells (the first course), and 3 weeks later, 6 g/m 2 of cyclophosphamide with 800 mg/m 2 of thiotepa by 96-hr infusion before marrow stem cell infusion (the second course). Whole blood cyclophosphamide and 4-hydroxycyclophosphamide/Aldophosphamide concentrations were measured by a GC-EIMS method using deuterium labeled compounds as internal standards. In addition, plasma and urine cyclophosphamide concentrations were determined by a GC assay. Whole blood concentrations of cyclophosphamide and 4-hydroxycyclophosphamide/Aldophosphamide vs. time data and urinary excretion of cyclophosphamide data from the first course were co-modeled using a one-compartment model with Michaelis-Menten saturable elimination in parallel with first-order renal elimination (N 5 7) or first-order metabolic and renal elimination (N 5 5) for cyclophosphamide and one-compartment model with first-order elimination for 4-hydroxycyclophosphamide/Aldophosphamide. The parallelism between cyclophosphamide and 4-hydroxycyclophosphamide/Aldophosphamide disposition curves implies that the pharmacokinetics of 4-hydroxycyclophosphamide/Aldophosphamide is formation limited; only the fractional 4-hydroxycyclophosphamide/ Aldophosphamide clearance rate (Clmet/Fmet) can be estimated. The mean Vmax and Km for cyclophosphamide were 0.78 mM/min and 247 mM, respectively. The mean nonrenal clearance (Clnr )o f cyclophosphamide for five patients with apparent first-order elimination of cyclophosphamide was 67 ml/min. The mean Clmet/Fmet of 4-hydroxycyclophosphamide/Aldophosphamide was 2982 ml/ min. The mean renal clearance (Clr) of cyclophosphamide was 29 ml/min and 24 ml/min for the first course and the second course, respectively. The correlations between cyclophosphamide AUCs and 4-hydroxycyclophosphamide/Aldophosphamide AUCs were sought for both drug courses. Blood and plasma cyclophosphamide concentrations were remarkably similar, indicating that cyclophosphamide partitions equally in the red cell and plasma volume. Computer simulation of the effect of potential alterations in Michaelis-Menten saturable elimination and renal clearance on 4-hydroxycyclophosphamide/Aldophosphamide has been used to illustrate the complex relationship between the exposure to parent compound and active metabolite.
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cyclophosphamide and 4 hydroxycyclophosphamide Aldophosphamide kinetics in patients receiving high dose cyclophosphamide chemotherapy
1996Co-Authors: Lawrence W Anderson, Tian Ling Chen, Louise B Grochow, O M Colvin, Jerry M Collins, M J Kennedy, John M StrongAbstract:Using a recently developed gas chromatography and mass spectrometry method to determine whole-blood cyclophosphamide (CP) and 4-hydroxycyclophosphamide/Aldophosphamide (4-HO-CP/AP) concentrations, we investigated their pharmacokinetics in women receiving CP therapy. Patients (n = 18) received one or two courses of CP: (a) a 90-min i.v. infusion (4 g/m2) followed by a 96-h i.v. infusion (6 g/m2) in combination with high-dose thiotepa; or (b) a 96-h i.v. infusion (6 g/m2) in combination with high-dose thiotepa. Whole-blood exposures to CP [area under the whole blood concentration versus time curve (AUCCP)] and 4-HO-CP/AP (AUC4HOCP) between courses 1 and 2 were compared after normalization to dose (g/m2). A nonproportional increase was observed for the AUCCP between the first course [1112 micrometer. h/g/m2 +/- 14% coefficient of variation (CV)] and the second course (1579 micrometer . h/g/m2 +/- 28% CV) (P
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cyclophosphamide and 4 hydroxycyclophosphamide Aldophosphamide kinetics in patients receiving high dose cyclophosphamide chemotherapy
1996Co-Authors: Lawrence W Anderson, Tian Ling Chen, Louise B Grochow, O M Colvin, Jerry M Collins, M J Kennedy, John M StrongAbstract:Using a recently developed gas chromatography and mass spectrometry method to determine whole-blood cyclophosphamide (CP) and 4-hydroxycyclophosphamide/Aldophosphamide (4-HO-CP/AP) concentrations, we investigated their pharmacokinetics in women receiving CP therapy. Patients (n = 18) received one or two courses of CP: (a) a 90-min i.v. infusion (4 g/m2) followed by a 96-h i.v. infusion (6 g/m2) in combination with high-dose thiotepa; or (b) a 96-h i.v. infusion (6 g/m2) in combination with high-dose thiotepa. Whole-blood exposures to CP [area under the whole blood concentration versus time curve (AUCCP)] and 4-HO-CP/AP (AUC4HOCP) between courses 1 and 2 were compared after normalization to dose (g/m2). A nonproportional increase was observed for the AUCCP between the first course [1112 micrometer. h/g/m2 +/- 14% coefficient of variation (CV)] and the second course (1579 micrometer . h/g/m2 +/- 28% CV) (P < 0.001). In contrast, the AUC4HOCP (27 micrometer . h/g/m2 +/- 25% CV) determined for the first course was 29% higher than the AUC4HOCP (21 micrometer . h/g/m2 +/- 26% CV) for the second course (P < 0.01). The interpatient whole-blood exposures to both CP and 4-HO-CP/AP were remarkably consistent in this patient population with percent CVs ranging from 14 to 28%. Because thiotepa (800 mg/m2) was administered simultaneously with CP during the second course of treatment, possible inhibition of CP metabolism by thiotepa was investigated using human liver microsomes in vitro. IC50 values determined for inhibition of CP metabolism in three individual liver donors ranged from 1.0 to 40 micrometer. However, the clinical relevance of this observation has not been established.
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quantitation of 4 hydroxycyclophosphamide Aldophosphamide in whole blood
1995Co-Authors: L W Anderson, Louise B Grochow, O M Colvin, Susan M. Ludeman, J M StrongAbstract:Abstract There is considerable interest in determining 4-hydroxycylcophosphamide/Aldophosphamide (4-HO-CP/AP) blood levels in patients receiving the prodrug, cyclophosphamide (CP). Phosphoramide mustard (PM), the alkylating metabolite of CP, is relatively impermeable to cell membranes and it is generally believed that circulating intermediary metabolites, including Aldophosphamide, the immediate precursor of PM, is transported by circulating blood to tumor tissue. Therefore, circulating 4-HO-CP/AP blood levels should more closely reflect the oncostatic and cytotoxic effects of CP than the parent drug. We have developed a gas chromatographic electron-impact mass spectrometric (GC-EIMS) method suitable for routine monitoring of 4-HO-CP/AP levels in whole blood over the range 0.085 μM (25 ng/ml) to 34 μM (10 μ/ml). The unstable metabolites were derivatized with O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine-HCl to form a stable Aldophosphamide oxime derivative (PBOX). [2H4]PBOX was used as an internal standard. For clinical samples, tubes were prepared prior to blood drawing, which contained the derivatizing reagent solution and the internal standard. These solutions were stable for up to 3 months when stored at room temperature. Following addition of blood to the reaction tubes, PBOX formation was rapid and the resulting derivative was stable under these conditions for up to 8 days at room temperature. Application of the method was demonstrated by quantitating 4-HO-CP/AP blood levels in patients receiving 4 g/m2 intravenous infusion of CP over a period of 90 min.