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Sarah L. Miles - One of the best experts on this subject based on the ideXlab platform.
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In vitro nephrotoxicity induced by N-(3,5-dichlorophenyl)succinimide (NDPS) metabolites in isolated renal cortical cells from male and female Fischer 344 rats: evidence for a nephrotoxic Sulfate Conjugate metabolite.
Toxicology, 2001Co-Authors: Gary O. Rankin, Suk K Hong, Dianne K. Anestis, Lawrence H. Lash, Sarah L. MilesAbstract:The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) induces nephrotoxicity in vivo that is characterized as acute polyuric renal failure and proximal tubular necrosis. However, earlier in vitro studies have failed to reproduce the in vivo nephrotoxicity seen with NDPS or its nephrotoxic metabolites N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA). The purpose of this study was to examine the nephrotoxic potential of NDPS, its known non-Conjugated metabolites, the O-Sulfate Conjugate of NDHS (NSC), and the putative metabolite N-(3,5-dichlorophenyl)maleimide (NDPM) and its hydrolysis product N-(3,5-dichlorophenyl)maleamic acid (NDPMA) using freshly isolated renal cortical cells (IRCC). IRCC were obtained from untreated male or female Fischer 344 rats following collagenase perfusion of the kidneys. Cells (approximately 4 million per ml) (N=4) were incubated with up to 1.0 mM NDPS or an NDPS metabolite or vehicle for up to 120 min. Cytotoxicity was determined by measuring lactate dehydrogenase (LDH) release into the medium. Only NSC (>0.5 mM) and NDPM (> or =0.5 mM) exposure increased LDH release from IRCC. NSC 1.0 mM or NDPM 0.5 mM increased LDH release from IRCC within 15--30 min of exposure. NDPS or the remaining NDPS metabolites did not increase LDH release at bath concentrations of 1.0 mM for exposures of 120 min. IRCC from male and female rats responded similarly to the toxic effects of NDPS and its metabolites. These results demonstrate that Sulfate Conjugates of NDPS metabolites can be fast acting nephrotoxicants and could contribute to NDPS nephrotoxicity in vivo. These results also suggest that the kidney probably accumulates toxic Sulfate Conjugates of NDPS metabolites rather than forming the Conjugates. In addition, mechanisms responsible for gender differences in nephrotoxicity seen with NDPS and NDPS metabolites in vivo either occur prior to renal accumulation of Sulfate Conjugates and/or represent biochemical/physiological differences between the genders.
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In vitro nephrotoxicity induced by N-(3,5-dichlorophenyl)succinimide (NDPS) metabolites in isolated renal cortical cells from male and female Fischer 344 rats: evidence for a nephrotoxic Sulfate Conjugate metabolite.
Toxicology, 2001Co-Authors: Gary O. Rankin, Suk K Hong, Dianne K. Anestis, Lawrence H. Lash, Sarah L. MilesAbstract:Abstract The agricultural fungicide N -(3,5-dichlorophenyl)succinimide (NDPS) induces nephrotoxicity in vivo that is characterized as acute polyuric renal failure and proximal tubular necrosis. However, earlier in vitro studies have failed to reproduce the in vivo nephrotoxicity seen with NDPS or its nephrotoxic metabolites N -(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N -(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA). The purpose of this study was to examine the nephrotoxic potential of NDPS, its known non-Conjugated metabolites, the O -Sulfate Conjugate of NDHS (NSC), and the putative metabolite N -(3,5-dichlorophenyl)maleimide (NDPM) and its hydrolysis product N -(3,5-dichlorophenyl)maleamic acid (NDPMA) using freshly isolated renal cortical cells (IRCC). IRCC were obtained from untreated male or female Fischer 344 rats following collagenase perfusion of the kidneys. Cells (∼4 million per ml) ( N =4) were incubated with up to 1.0 mM NDPS or an NDPS metabolite or vehicle for up to 120 min. Cytotoxicity was determined by measuring lactate dehydrogenase (LDH) release into the medium. Only NSC (>0.5 mM) and NDPM (≥0.5 mM) exposure increased LDH release from IRCC. NSC 1.0 mM or NDPM 0.5 mM increased LDH release from IRCC within 15–30 min of exposure. NDPS or the remaining NDPS metabolites did not increase LDH release at bath concentrations of 1.0 mM for exposures of 120 min. IRCC from male and female rats responded similarly to the toxic effects of NDPS and its metabolites. These results demonstrate that Sulfate Conjugates of NDPS metabolites can be fast acting nephrotoxicants and could contribute to NDPS nephrotoxicity in vivo. These results also suggest that the kidney probably accumulates toxic Sulfate Conjugates of NDPS metabolites rather than forming the Conjugates. In addition, mechanisms responsible for gender differences in nephrotoxicity seen with NDPS and NDPS metabolites in vivo either occur prior to renal accumulation of Sulfate Conjugates and/or represent biochemical/physiological differences between the genders.
Jeffrey R Koup - One of the best experts on this subject based on the ideXlab platform.
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Clinical Pharmacokinetics of Troglitazone
Clinical Pharmacokinetics, 1999Co-Authors: Malcolm Young, Artemios B Vassos, Edward J. Randinitis, Jeffrey R KoupAbstract:Troglitazone is a new thiazolidinedione oral antidiabetic agent approved for use to improve glycaemic control in patients with type 2 diabetes. It is rapidly absorbed with an absolute bioavailability of between 40 and 50%. Food increases the absorption by 30 to 80%. The pharmacokinetics of troglitazone are linear over the clinical dosage range of 200 to 600mg once daily. The mean elimination half-life ranges from 7.6 to 24 hours, which facilitates a once daily administration regimen. The pharmacokinetics of troglitazone are similar between patients with type 2 diabetes and healthy individuals. In humans, troglitazone undergoes metabolism by sulfation, glucuronidation and oxidation to form a Sulfate Conjugate (M1), glucuronide Conjugate (M2) and quinone metabolite (M3), respectively. M1 and M3 are the major metabolites in plasma, and M2 is a minor metabolite. Age, gender, type 2 diabetes, renal impairment, smoking and race do not appear to influence the pharmacokinetics of troglitazone and its 2 major metabolites. In patients with hepatic impairment the plasma concentrations of troglitazone, M1 and M3 increase by 30%, 4-fold, and 2-fold, respectively. Cholestyramine decreases the absorption of troglitazone by 70%. Troglitazone may enhance the activities of cytochrome P450 (CYP) 3A and/or transporter(s) thereby reducing the plasma concentrations of terfenadine, cyclosporin, atorvastatin and fexofenadine. It also reduces the plasma concentrations of the oral contraceptive hormones ethinylestradiol, norethindrone and levonorgestrel. Troglitazone does not alter the pharmacokinetics of digoxin, glibenclamide (glyburide) or paracetamol (acetaminophen). There is no pharmacodynamic interaction between troglitazone and warfarin or alcohol (ethanol). Pharmacodynamic modelling showed that improvement in fasting glucose and triglyceride levels increased with dose from 200 to 600mg. Knowledge of systemic troglitazone exposure within a dose group does not improve the prediction of glucose lowering response or adverse effects beyond those based on the administered dose.
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Steady-state pharmacokinetics and dose proportionality of troglitazone and its metabolites
Journal of clinical pharmacology, 1999Co-Authors: Cho-ming Loi, Artemios B Vassos, Allen J Sedman, Edward J. Randinitis, Christine W. Alvey, Jeffrey R KoupAbstract:This study evaluated the steady-state pharmacokinetics and dose proportionality of troglitazone, metabolite 1 (Sulfate Conjugate), and metabolite 3 (quinone metabolite) following administration of daily oral doses of 200, 400, and 600mg troglitazonefor 7 days (per dosing period) to 21 subjects. During each dosing period, plasma samples were collected predose on days 1, 5, 6, and 7 and serially for 24 hours on day 7. Steady-state plasma concentrations for troglitazone, metabolite 1, and metabolite 3 were achieved by day 7. Troglitazone was rapidly absorbed with mean t max values of2. 7 to 2. 9 hours. Mean C max and AUC (0-24) values for troglitazone, metabolite 1, and metabolite 3 increased proportionally with increasing troglitazone doses over the clinical dose range of 200 mg to 600 mg administered once daily. Mean troglitazone CL/F, percent fluctuation, and AUC ratios of metabolite 1 and metabolite 3 to troglitazone were similar across dose groups. These data suggest that the pharmacokinetics and disposition of troglitazone and its metabolites are independent of dose over the dose range studied. Thus, troglitazone, metabolite 1, and metabolite 3 displayed linear pharmacokinetics at steady-state.
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Lack of Effect of Type II Diabetes on the Pharmacokinetics of Troglitazone in a Multiple‐Dose Study
Journal of clinical pharmacology, 1997Co-Authors: Cho-ming Loi, Artemios B Vassos, Jeffrey R Koup, Edward J. Randinitis, David J. Kazierad, Allen J SedmanAbstract:Twelve patients with type II diabetes and 12 age-, weight-, and gender-matched healthy subjects participated in a study comparing the pharmacokinetics of troglitazone, metabolite 1 (Sulfate Conjugate), and metabolite 3 (quinone) after oral administration of 400 mg of troglitazone every morning for 15 days. Serial plasma samples collected after the dose on days 1 and 15 were analyzed for troglitazone, metabolite 1, and metabolite 3 using a validated HPLC method. Steady state plasma concentrations of troglitazone and its metabolites were achieved by the fifth day of troglitazone administration in both groups. Mean day 15 Cmax, tmax, AUC0-24, and Cl/F values of troglitazone were 1.54 micrograms/mL, 3.25 hours, 15.6 micrograms.hr/mL, and 461 mL/min, respectively, in patients with type II diabetes. Corresponding parameter values were 1.42 micrograms/mL, 2.63 hours, 12.5 micrograms.hr/mL, and 558 mL/min, respectively, in healthy subjects. Elimination t1/2 was approximately 24 hours in both groups. Mean day 15 pharmacokinetic parameter values for metabolite 1 and metabolite 3 were similar in the two groups. Ratio of AUC of metabolite 1 to troglitazone was 6.2 and 6.7, respectively, in patients and in healthy subjects. Ratio of AUC of metabolite 3 to troglitazone was 1.1 in both groups. Thus, steady-state pharmacokinetics and disposition of troglitazone and its metabolites in patients with type II diabetes were similar to those in healthy subjects.
Cho-ming Loi - One of the best experts on this subject based on the ideXlab platform.
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Steady-state pharmacokinetics and dose proportionality of troglitazone and its metabolites
Journal of clinical pharmacology, 1999Co-Authors: Cho-ming Loi, Artemios B Vassos, Allen J Sedman, Edward J. Randinitis, Christine W. Alvey, Jeffrey R KoupAbstract:This study evaluated the steady-state pharmacokinetics and dose proportionality of troglitazone, metabolite 1 (Sulfate Conjugate), and metabolite 3 (quinone metabolite) following administration of daily oral doses of 200, 400, and 600mg troglitazonefor 7 days (per dosing period) to 21 subjects. During each dosing period, plasma samples were collected predose on days 1, 5, 6, and 7 and serially for 24 hours on day 7. Steady-state plasma concentrations for troglitazone, metabolite 1, and metabolite 3 were achieved by day 7. Troglitazone was rapidly absorbed with mean t max values of2. 7 to 2. 9 hours. Mean C max and AUC (0-24) values for troglitazone, metabolite 1, and metabolite 3 increased proportionally with increasing troglitazone doses over the clinical dose range of 200 mg to 600 mg administered once daily. Mean troglitazone CL/F, percent fluctuation, and AUC ratios of metabolite 1 and metabolite 3 to troglitazone were similar across dose groups. These data suggest that the pharmacokinetics and disposition of troglitazone and its metabolites are independent of dose over the dose range studied. Thus, troglitazone, metabolite 1, and metabolite 3 displayed linear pharmacokinetics at steady-state.
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Lack of Effect of Type II Diabetes on the Pharmacokinetics of Troglitazone in a Multiple‐Dose Study
Journal of clinical pharmacology, 1997Co-Authors: Cho-ming Loi, Artemios B Vassos, Jeffrey R Koup, Edward J. Randinitis, David J. Kazierad, Allen J SedmanAbstract:Twelve patients with type II diabetes and 12 age-, weight-, and gender-matched healthy subjects participated in a study comparing the pharmacokinetics of troglitazone, metabolite 1 (Sulfate Conjugate), and metabolite 3 (quinone) after oral administration of 400 mg of troglitazone every morning for 15 days. Serial plasma samples collected after the dose on days 1 and 15 were analyzed for troglitazone, metabolite 1, and metabolite 3 using a validated HPLC method. Steady state plasma concentrations of troglitazone and its metabolites were achieved by the fifth day of troglitazone administration in both groups. Mean day 15 Cmax, tmax, AUC0-24, and Cl/F values of troglitazone were 1.54 micrograms/mL, 3.25 hours, 15.6 micrograms.hr/mL, and 461 mL/min, respectively, in patients with type II diabetes. Corresponding parameter values were 1.42 micrograms/mL, 2.63 hours, 12.5 micrograms.hr/mL, and 558 mL/min, respectively, in healthy subjects. Elimination t1/2 was approximately 24 hours in both groups. Mean day 15 pharmacokinetic parameter values for metabolite 1 and metabolite 3 were similar in the two groups. Ratio of AUC of metabolite 1 to troglitazone was 6.2 and 6.7, respectively, in patients and in healthy subjects. Ratio of AUC of metabolite 3 to troglitazone was 1.1 in both groups. Thus, steady-state pharmacokinetics and disposition of troglitazone and its metabolites in patients with type II diabetes were similar to those in healthy subjects.
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Meta‐Analysis of Steady‐State Pharmacokinetics of Troglitazone and Its Metabolites
Journal of clinical pharmacology, 1997Co-Authors: Cho-ming Loi, Edward J. Randinitis, Christine W. Alvey, Robert B. Abel, Malcolm A. YoungAbstract:The object of this study is to evaluate the effects of age, gender, age-by-gender interaction, Type II diabetes, body weight, race, smoking, and formulation on steady-state pharmacokinetics of troglitazone, Metabolite 1 (Sulfate Conjugate), and Metabolite 3 (quinone metabolite) following multiple-dose oral administration of troglitazone. Pharmacokinetic parameter estimates [Cl/F (apparent oral clearance), AUC 0-24 (area under plasma concentration-time curve), and ratio of AUC for troglitazone to Metabolite 1 and to Metabolite 3] obtained from 84 healthy volunteers and 171 patients with Type II diabetes in 8 studies were analyzed using a graphical method (for race and smoking) or a weighted ANCOVA model incorporating gender, health status (healthy vs Type II diabetes), and formulation as main effects; age, age-by-gender interaction, and body weight as continuous covariates. Ratio of AUC for troglitazone to metabolites was also examined by inspection of log-probit plots. Age, gender, age-by-gender, Type II diabetes, and formulation had negligible effects on troglitazone Cl/F, AUC 0-24 (all analytes), and AUC ratio of troglitazone to metabolites. Race and smoking did not appear to influence steady-state pharmacokinetics of troglitazone and its metabolites. Although body weight was a significant covariate for AUC 0-24 and Cl/F, the explanatory power of the overall model was weak (R 2 < 0.2). Log-probit plots did not reveal a polymorphic distribution in A UC ratio of troglitazone to Metabolite I or Metabolite 3. Based on pharmacokinetics, dose adjustment for troglitazone in relation to the demographic factors examined is not required due to their poor predictive ability on steady-state pharmacokinetics of troglitazone and its metabolites.
Edward J. Randinitis - One of the best experts on this subject based on the ideXlab platform.
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Clinical Pharmacokinetics of Troglitazone
Clinical Pharmacokinetics, 1999Co-Authors: Malcolm Young, Artemios B Vassos, Edward J. Randinitis, Jeffrey R KoupAbstract:Troglitazone is a new thiazolidinedione oral antidiabetic agent approved for use to improve glycaemic control in patients with type 2 diabetes. It is rapidly absorbed with an absolute bioavailability of between 40 and 50%. Food increases the absorption by 30 to 80%. The pharmacokinetics of troglitazone are linear over the clinical dosage range of 200 to 600mg once daily. The mean elimination half-life ranges from 7.6 to 24 hours, which facilitates a once daily administration regimen. The pharmacokinetics of troglitazone are similar between patients with type 2 diabetes and healthy individuals. In humans, troglitazone undergoes metabolism by sulfation, glucuronidation and oxidation to form a Sulfate Conjugate (M1), glucuronide Conjugate (M2) and quinone metabolite (M3), respectively. M1 and M3 are the major metabolites in plasma, and M2 is a minor metabolite. Age, gender, type 2 diabetes, renal impairment, smoking and race do not appear to influence the pharmacokinetics of troglitazone and its 2 major metabolites. In patients with hepatic impairment the plasma concentrations of troglitazone, M1 and M3 increase by 30%, 4-fold, and 2-fold, respectively. Cholestyramine decreases the absorption of troglitazone by 70%. Troglitazone may enhance the activities of cytochrome P450 (CYP) 3A and/or transporter(s) thereby reducing the plasma concentrations of terfenadine, cyclosporin, atorvastatin and fexofenadine. It also reduces the plasma concentrations of the oral contraceptive hormones ethinylestradiol, norethindrone and levonorgestrel. Troglitazone does not alter the pharmacokinetics of digoxin, glibenclamide (glyburide) or paracetamol (acetaminophen). There is no pharmacodynamic interaction between troglitazone and warfarin or alcohol (ethanol). Pharmacodynamic modelling showed that improvement in fasting glucose and triglyceride levels increased with dose from 200 to 600mg. Knowledge of systemic troglitazone exposure within a dose group does not improve the prediction of glucose lowering response or adverse effects beyond those based on the administered dose.
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Steady-state pharmacokinetics and dose proportionality of troglitazone and its metabolites
Journal of clinical pharmacology, 1999Co-Authors: Cho-ming Loi, Artemios B Vassos, Allen J Sedman, Edward J. Randinitis, Christine W. Alvey, Jeffrey R KoupAbstract:This study evaluated the steady-state pharmacokinetics and dose proportionality of troglitazone, metabolite 1 (Sulfate Conjugate), and metabolite 3 (quinone metabolite) following administration of daily oral doses of 200, 400, and 600mg troglitazonefor 7 days (per dosing period) to 21 subjects. During each dosing period, plasma samples were collected predose on days 1, 5, 6, and 7 and serially for 24 hours on day 7. Steady-state plasma concentrations for troglitazone, metabolite 1, and metabolite 3 were achieved by day 7. Troglitazone was rapidly absorbed with mean t max values of2. 7 to 2. 9 hours. Mean C max and AUC (0-24) values for troglitazone, metabolite 1, and metabolite 3 increased proportionally with increasing troglitazone doses over the clinical dose range of 200 mg to 600 mg administered once daily. Mean troglitazone CL/F, percent fluctuation, and AUC ratios of metabolite 1 and metabolite 3 to troglitazone were similar across dose groups. These data suggest that the pharmacokinetics and disposition of troglitazone and its metabolites are independent of dose over the dose range studied. Thus, troglitazone, metabolite 1, and metabolite 3 displayed linear pharmacokinetics at steady-state.
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Lack of Effect of Type II Diabetes on the Pharmacokinetics of Troglitazone in a Multiple‐Dose Study
Journal of clinical pharmacology, 1997Co-Authors: Cho-ming Loi, Artemios B Vassos, Jeffrey R Koup, Edward J. Randinitis, David J. Kazierad, Allen J SedmanAbstract:Twelve patients with type II diabetes and 12 age-, weight-, and gender-matched healthy subjects participated in a study comparing the pharmacokinetics of troglitazone, metabolite 1 (Sulfate Conjugate), and metabolite 3 (quinone) after oral administration of 400 mg of troglitazone every morning for 15 days. Serial plasma samples collected after the dose on days 1 and 15 were analyzed for troglitazone, metabolite 1, and metabolite 3 using a validated HPLC method. Steady state plasma concentrations of troglitazone and its metabolites were achieved by the fifth day of troglitazone administration in both groups. Mean day 15 Cmax, tmax, AUC0-24, and Cl/F values of troglitazone were 1.54 micrograms/mL, 3.25 hours, 15.6 micrograms.hr/mL, and 461 mL/min, respectively, in patients with type II diabetes. Corresponding parameter values were 1.42 micrograms/mL, 2.63 hours, 12.5 micrograms.hr/mL, and 558 mL/min, respectively, in healthy subjects. Elimination t1/2 was approximately 24 hours in both groups. Mean day 15 pharmacokinetic parameter values for metabolite 1 and metabolite 3 were similar in the two groups. Ratio of AUC of metabolite 1 to troglitazone was 6.2 and 6.7, respectively, in patients and in healthy subjects. Ratio of AUC of metabolite 3 to troglitazone was 1.1 in both groups. Thus, steady-state pharmacokinetics and disposition of troglitazone and its metabolites in patients with type II diabetes were similar to those in healthy subjects.
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Meta‐Analysis of Steady‐State Pharmacokinetics of Troglitazone and Its Metabolites
Journal of clinical pharmacology, 1997Co-Authors: Cho-ming Loi, Edward J. Randinitis, Christine W. Alvey, Robert B. Abel, Malcolm A. YoungAbstract:The object of this study is to evaluate the effects of age, gender, age-by-gender interaction, Type II diabetes, body weight, race, smoking, and formulation on steady-state pharmacokinetics of troglitazone, Metabolite 1 (Sulfate Conjugate), and Metabolite 3 (quinone metabolite) following multiple-dose oral administration of troglitazone. Pharmacokinetic parameter estimates [Cl/F (apparent oral clearance), AUC 0-24 (area under plasma concentration-time curve), and ratio of AUC for troglitazone to Metabolite 1 and to Metabolite 3] obtained from 84 healthy volunteers and 171 patients with Type II diabetes in 8 studies were analyzed using a graphical method (for race and smoking) or a weighted ANCOVA model incorporating gender, health status (healthy vs Type II diabetes), and formulation as main effects; age, age-by-gender interaction, and body weight as continuous covariates. Ratio of AUC for troglitazone to metabolites was also examined by inspection of log-probit plots. Age, gender, age-by-gender, Type II diabetes, and formulation had negligible effects on troglitazone Cl/F, AUC 0-24 (all analytes), and AUC ratio of troglitazone to metabolites. Race and smoking did not appear to influence steady-state pharmacokinetics of troglitazone and its metabolites. Although body weight was a significant covariate for AUC 0-24 and Cl/F, the explanatory power of the overall model was weak (R 2 < 0.2). Log-probit plots did not reveal a polymorphic distribution in A UC ratio of troglitazone to Metabolite I or Metabolite 3. Based on pharmacokinetics, dose adjustment for troglitazone in relation to the demographic factors examined is not required due to their poor predictive ability on steady-state pharmacokinetics of troglitazone and its metabolites.
Gary O. Rankin - One of the best experts on this subject based on the ideXlab platform.
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In vitro nephrotoxicity induced by N-(3,5-dichlorophenyl)succinimide (NDPS) metabolites in isolated renal cortical cells from male and female Fischer 344 rats: evidence for a nephrotoxic Sulfate Conjugate metabolite.
Toxicology, 2001Co-Authors: Gary O. Rankin, Suk K Hong, Dianne K. Anestis, Lawrence H. Lash, Sarah L. MilesAbstract:The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) induces nephrotoxicity in vivo that is characterized as acute polyuric renal failure and proximal tubular necrosis. However, earlier in vitro studies have failed to reproduce the in vivo nephrotoxicity seen with NDPS or its nephrotoxic metabolites N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA). The purpose of this study was to examine the nephrotoxic potential of NDPS, its known non-Conjugated metabolites, the O-Sulfate Conjugate of NDHS (NSC), and the putative metabolite N-(3,5-dichlorophenyl)maleimide (NDPM) and its hydrolysis product N-(3,5-dichlorophenyl)maleamic acid (NDPMA) using freshly isolated renal cortical cells (IRCC). IRCC were obtained from untreated male or female Fischer 344 rats following collagenase perfusion of the kidneys. Cells (approximately 4 million per ml) (N=4) were incubated with up to 1.0 mM NDPS or an NDPS metabolite or vehicle for up to 120 min. Cytotoxicity was determined by measuring lactate dehydrogenase (LDH) release into the medium. Only NSC (>0.5 mM) and NDPM (> or =0.5 mM) exposure increased LDH release from IRCC. NSC 1.0 mM or NDPM 0.5 mM increased LDH release from IRCC within 15--30 min of exposure. NDPS or the remaining NDPS metabolites did not increase LDH release at bath concentrations of 1.0 mM for exposures of 120 min. IRCC from male and female rats responded similarly to the toxic effects of NDPS and its metabolites. These results demonstrate that Sulfate Conjugates of NDPS metabolites can be fast acting nephrotoxicants and could contribute to NDPS nephrotoxicity in vivo. These results also suggest that the kidney probably accumulates toxic Sulfate Conjugates of NDPS metabolites rather than forming the Conjugates. In addition, mechanisms responsible for gender differences in nephrotoxicity seen with NDPS and NDPS metabolites in vivo either occur prior to renal accumulation of Sulfate Conjugates and/or represent biochemical/physiological differences between the genders.
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In vitro nephrotoxicity induced by N-(3,5-dichlorophenyl)succinimide (NDPS) metabolites in isolated renal cortical cells from male and female Fischer 344 rats: evidence for a nephrotoxic Sulfate Conjugate metabolite.
Toxicology, 2001Co-Authors: Gary O. Rankin, Suk K Hong, Dianne K. Anestis, Lawrence H. Lash, Sarah L. MilesAbstract:Abstract The agricultural fungicide N -(3,5-dichlorophenyl)succinimide (NDPS) induces nephrotoxicity in vivo that is characterized as acute polyuric renal failure and proximal tubular necrosis. However, earlier in vitro studies have failed to reproduce the in vivo nephrotoxicity seen with NDPS or its nephrotoxic metabolites N -(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N -(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA). The purpose of this study was to examine the nephrotoxic potential of NDPS, its known non-Conjugated metabolites, the O -Sulfate Conjugate of NDHS (NSC), and the putative metabolite N -(3,5-dichlorophenyl)maleimide (NDPM) and its hydrolysis product N -(3,5-dichlorophenyl)maleamic acid (NDPMA) using freshly isolated renal cortical cells (IRCC). IRCC were obtained from untreated male or female Fischer 344 rats following collagenase perfusion of the kidneys. Cells (∼4 million per ml) ( N =4) were incubated with up to 1.0 mM NDPS or an NDPS metabolite or vehicle for up to 120 min. Cytotoxicity was determined by measuring lactate dehydrogenase (LDH) release into the medium. Only NSC (>0.5 mM) and NDPM (≥0.5 mM) exposure increased LDH release from IRCC. NSC 1.0 mM or NDPM 0.5 mM increased LDH release from IRCC within 15–30 min of exposure. NDPS or the remaining NDPS metabolites did not increase LDH release at bath concentrations of 1.0 mM for exposures of 120 min. IRCC from male and female rats responded similarly to the toxic effects of NDPS and its metabolites. These results demonstrate that Sulfate Conjugates of NDPS metabolites can be fast acting nephrotoxicants and could contribute to NDPS nephrotoxicity in vivo. These results also suggest that the kidney probably accumulates toxic Sulfate Conjugates of NDPS metabolites rather than forming the Conjugates. In addition, mechanisms responsible for gender differences in nephrotoxicity seen with NDPS and NDPS metabolites in vivo either occur prior to renal accumulation of Sulfate Conjugates and/or represent biochemical/physiological differences between the genders.
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synthesis of n 3 5 dichlorophenyl 2 hydroxysuccinimide o Sulfate a potential metabolite of the nephrotoxicant n 3 5 dichlorophenyl succinimide
Journal of Heterocyclic Chemistry, 1995Co-Authors: Suk K Hong, Gary O. Rankin, K R ScottAbstract:The Sulfate Conjugate 2 of N-(3,5-dichlorophenyl)-2-hydroxysuccinimide, a potential metabolite of the nephrotoxicant N-(3,5-dichlorophenyl)succinimide, is prepared from the 2-hydroxysuccinimide (1) by the reaction with chlorosulfonic acid in chloroform and ether mixture at −78°.
