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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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Effect of Troglitazone on the pharmacokinetics of an oral contraceptive agent.
Journal of clinical pharmacology, 1999Co-Authors: Cho-ming Loi, Ralph H Stern, Artemios B Vassos, Philip W Knowlton, J. R. Koup, Allen J SedmanAbstract:Fifteen healthy women participated in a study to determine the effect of multiple doses of Troglitazone on the pharmacokinetics of Ortho-Novum 1/35 (35 micrograms ethinyl estradiol [EE] and 1 mg norethindrone [NE]). Participants received three cycles (21 days each of active drug followed by 7 days without medication) of Ortho-Novum. During the third cycle, participants also received Troglitazone 600 mg qd for 22 days. Pharmacokinetic profiles of EE and NE were determined on day 21 of the second and third cycles. Progesterone and sex hormone binding globulin (SHBG) levels were also measured. Troglitazone decreased EE Cmax and AUC(0-24) by 32% and 29%, respectively. Likewise, Troglitazone decreased NE Cmax and AUC(0-24) by 31% and 30%, respectively. Plasma SHBG concentrations increased from 113 nmol/L during cycle 2 to 220 nmol/L during cycle 3. Troglitazone reduced plasma unbound AUC for NE by 49%. Serum progesterone levels were lower than 1.5 ng/mL on all occasions. Thus, coadministration of Troglitazone and Ortho-Novum decreases the systemic exposure to EE and NE. A higher dose of oral contraceptive or an alternate method of contraception should be considered for patients treated with Troglitazone.
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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. Young, J. R. KoupAbstract: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.
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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effect of Troglitazone on the pharmacokinetics of an oral contraceptive agent
The Journal of Clinical Pharmacology, 1999Co-Authors: Ralph H Stern, Artemios B Vassos, Philip W Knowlton, Jeffrey R Koup, Allen J SedmanAbstract:15 healthy women participated in a study to determine the effect of multiple doses of Troglitazone on the pharmacokinetics of Ortho-Novum 1/35 (35 mcg ethinyl estradiol [EE] and 1 mg norethindrone [NE]). Participants received three cycles (21 days each of active drug followed by 7 days without medication) of Ortho-Novum. During the third cycle participants also received Troglitazone at 600 mg 4 times daily for 22 days. Pharmacokinetic profiles of EE and NE were determined on day 21 of the second and third cycles. Progesterone and sex hormone binding globulin (SHBG) levels were also measured. Troglitazone decreased EE maximum plasma concentrations (Cmax) and area under plasma concentration (AUC)(0-24) by 32% and 29% respectively. Likewise Troglitazone decreased NE Cmax and AUC(0-24) by 31% and 30% respectively. Plasma SHBG concentrations increased from 113 nmol/l during cycle 2 to 220 nmol/l during cycle 3. Troglitazone reduced plasma unbound AUC for NE by 49%. Serum progesterone levels were lower than 1.5 ng/ml on all occasions. Thus co-administration of Troglitazone and Ortho-Novum decreases the systemic exposure to EE and NE. A higher dose of oral contraceptive or an alternate method of contraception should be considered for patients with Troglitazone. (authors)
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Pharmacokinetics of Troglitazone in Patients with Renal Insufficiency
Clinical Drug Investigation, 1999Co-Authors: Philip W Knowlton, Artemios B Vassos, Allen J Sedman, Robert A. Blum, Joanne I. Brodfuehrer, Edward J. Randinitis, Jeffrey R KoupAbstract:Objective: The pharmacokinetic profiles of Troglitazone and two metabolites were evaluated following a single 400mg oral dose of Troglitazone in 20 patients with various degrees of renal function. Methods: Plasma Troglitazone and metabolite concentrations were determined by high performance liquid chromatography, and Troglitazone free fraction was determined by ultracentrifugation. Results: Mean maximum plasma concentration and area under the curve for total Troglitazone appeared lower in patients with severe renal impairment (SRI) compared with those with normal renal function (NRF). Troglitazone free fraction was higher in patients with SRI (4.85%) than in subjects with NRF (1.66%), producing similar exposure values for unbound Troglitazone, the moiety presumed to exert the pharmacological effect. Regression analysis revealed poor correlations of creatinine clearance value with total Troglitazone, unbound Troglitazone, and metabolite pharmacokinetic parameter values. Conclusion: These data indicated that renal function does not predict Troglitazone pharmacokinetics and systemic exposure to unbound Troglitazone is unaltered with renal impairment. Thus, Troglitazone dose adjustment based on pharmacokinetics is not required in patients with renal insufficiency.
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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.
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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Pharmacokinetics of Troglitazone in Patients with Renal Insufficiency
Clinical Drug Investigation, 1999Co-Authors: Philip W Knowlton, Artemios B Vassos, Allen J Sedman, Robert A. Blum, Joanne I. Brodfuehrer, Edward J. Randinitis, Jeffrey R KoupAbstract:Objective: The pharmacokinetic profiles of Troglitazone and two metabolites were evaluated following a single 400mg oral dose of Troglitazone in 20 patients with various degrees of renal function. Methods: Plasma Troglitazone and metabolite concentrations were determined by high performance liquid chromatography, and Troglitazone free fraction was determined by ultracentrifugation. Results: Mean maximum plasma concentration and area under the curve for total Troglitazone appeared lower in patients with severe renal impairment (SRI) compared with those with normal renal function (NRF). Troglitazone free fraction was higher in patients with SRI (4.85%) than in subjects with NRF (1.66%), producing similar exposure values for unbound Troglitazone, the moiety presumed to exert the pharmacological effect. Regression analysis revealed poor correlations of creatinine clearance value with total Troglitazone, unbound Troglitazone, and metabolite pharmacokinetic parameter values. Conclusion: These data indicated that renal function does not predict Troglitazone pharmacokinetics and systemic exposure to unbound Troglitazone is unaltered with renal impairment. Thus, Troglitazone dose adjustment based on pharmacokinetics is not required in patients with renal insufficiency.
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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. Young, J. R. KoupAbstract: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.
Allen J Sedman - One of the best experts on this subject based on the ideXlab platform.
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effect of Troglitazone on the pharmacokinetics of an oral contraceptive agent
The Journal of Clinical Pharmacology, 1999Co-Authors: Ralph H Stern, Artemios B Vassos, Philip W Knowlton, Jeffrey R Koup, Allen J SedmanAbstract:15 healthy women participated in a study to determine the effect of multiple doses of Troglitazone on the pharmacokinetics of Ortho-Novum 1/35 (35 mcg ethinyl estradiol [EE] and 1 mg norethindrone [NE]). Participants received three cycles (21 days each of active drug followed by 7 days without medication) of Ortho-Novum. During the third cycle participants also received Troglitazone at 600 mg 4 times daily for 22 days. Pharmacokinetic profiles of EE and NE were determined on day 21 of the second and third cycles. Progesterone and sex hormone binding globulin (SHBG) levels were also measured. Troglitazone decreased EE maximum plasma concentrations (Cmax) and area under plasma concentration (AUC)(0-24) by 32% and 29% respectively. Likewise Troglitazone decreased NE Cmax and AUC(0-24) by 31% and 30% respectively. Plasma SHBG concentrations increased from 113 nmol/l during cycle 2 to 220 nmol/l during cycle 3. Troglitazone reduced plasma unbound AUC for NE by 49%. Serum progesterone levels were lower than 1.5 ng/ml on all occasions. Thus co-administration of Troglitazone and Ortho-Novum decreases the systemic exposure to EE and NE. A higher dose of oral contraceptive or an alternate method of contraception should be considered for patients with Troglitazone. (authors)
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Pharmacokinetics of Troglitazone in Patients with Renal Insufficiency
Clinical Drug Investigation, 1999Co-Authors: Philip W Knowlton, Artemios B Vassos, Allen J Sedman, Robert A. Blum, Joanne I. Brodfuehrer, Edward J. Randinitis, Jeffrey R KoupAbstract:Objective: The pharmacokinetic profiles of Troglitazone and two metabolites were evaluated following a single 400mg oral dose of Troglitazone in 20 patients with various degrees of renal function. Methods: Plasma Troglitazone and metabolite concentrations were determined by high performance liquid chromatography, and Troglitazone free fraction was determined by ultracentrifugation. Results: Mean maximum plasma concentration and area under the curve for total Troglitazone appeared lower in patients with severe renal impairment (SRI) compared with those with normal renal function (NRF). Troglitazone free fraction was higher in patients with SRI (4.85%) than in subjects with NRF (1.66%), producing similar exposure values for unbound Troglitazone, the moiety presumed to exert the pharmacological effect. Regression analysis revealed poor correlations of creatinine clearance value with total Troglitazone, unbound Troglitazone, and metabolite pharmacokinetic parameter values. Conclusion: These data indicated that renal function does not predict Troglitazone pharmacokinetics and systemic exposure to unbound Troglitazone is unaltered with renal impairment. Thus, Troglitazone dose adjustment based on pharmacokinetics is not required in patients with renal insufficiency.
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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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Effect of Troglitazone on the pharmacokinetics of an oral contraceptive agent.
Journal of clinical pharmacology, 1999Co-Authors: Cho-ming Loi, Ralph H Stern, Artemios B Vassos, Philip W Knowlton, J. R. Koup, Allen J SedmanAbstract:Fifteen healthy women participated in a study to determine the effect of multiple doses of Troglitazone on the pharmacokinetics of Ortho-Novum 1/35 (35 micrograms ethinyl estradiol [EE] and 1 mg norethindrone [NE]). Participants received three cycles (21 days each of active drug followed by 7 days without medication) of Ortho-Novum. During the third cycle, participants also received Troglitazone 600 mg qd for 22 days. Pharmacokinetic profiles of EE and NE were determined on day 21 of the second and third cycles. Progesterone and sex hormone binding globulin (SHBG) levels were also measured. Troglitazone decreased EE Cmax and AUC(0-24) by 32% and 29%, respectively. Likewise, Troglitazone decreased NE Cmax and AUC(0-24) by 31% and 30%, respectively. Plasma SHBG concentrations increased from 113 nmol/L during cycle 2 to 220 nmol/L during cycle 3. Troglitazone reduced plasma unbound AUC for NE by 49%. Serum progesterone levels were lower than 1.5 ng/mL on all occasions. Thus, coadministration of Troglitazone and Ortho-Novum decreases the systemic exposure to EE and NE. A higher dose of oral contraceptive or an alternate method of contraception should be considered for patients treated with Troglitazone.
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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.
Takao Kawasaki - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of solid state form of Troglitazone by solid state NMR spectroscopy
Journal of Pharmaceutical and Biomedical Analysis, 2005Co-Authors: Nobuyuki Suzuki, Takao KawasakiAbstract:The solid state forms of Troglitazone drug substance and diastereomers were characterized using solid state nuclear magnetic resonance (SSNMR) spectroscopic method. The SSNMR spectroscopy could distinguish the hydrated and the non-hydrated RR/SS forms more clearly than powder X-ray diffractometry (PXRD). The SSNMR result supported that Troglitazone drug substance consists of diastereomers as a simple physical mixture. SSNMR spectroscopy was also able to characterize the solid state forms of Troglitazone in tablets while PXRD was unable to because of interference from the pharmaceutical additives. Troglitazone was proved to exist in amorphous form in tablets, and keep its solid state form amorphous against heat and humidity. SSNMR spectroscopy thus provides very important information for the development of the pharmaceutical formulation of Troglitazone.
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Solid-State Variation of Troglitazone Drug Substance by Using a Different Recrystallization Method
Drug development and industrial pharmacy, 2003Co-Authors: Nobuyuki Suzuki, Ko Kasahara, Yoshiaki Watanabe, Suzue Kinoshita, Hirokazu Hasegawa, Takao KawasakiAbstract:Rapid and slow crystallization methods (A and B) were applied for Troglitazone, an equal mixture of four stereoisomers. Differences in the powder x-ray diffractometry patterns and hygroscopic patterns were observed among the samples crystallized by these methods, suggesting that Troglitazone has solid-state variation. In this article, Troglitazone recrystallized by method A was evaluated to clarify its structural characteristics and physical property. The crystal structure of predried Troglitazone recrystallized by method A was proved to be a dihydrate. By drying, it changed reversibly to an anhydrate, which is the same structure as the RS/SR form, keeping the same enantiomer ratio. The solubility of the Troglitazone by method A higher than that by method B at all enantiomer levels. But making the Troglitazone amorphous equalized the enantiomeric solubilities of the substances by both methods as well as increased the intrinsic solubilities. Troglitazone by both methods was proved to be stable and retained the ratio of the stereoisomers.
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Physical property of Troglitazone, an equal mixture of four stereoisomers.
International Journal of Pharmaceutics, 2002Co-Authors: Nobuyuki Suzuki, Ko Kasahara, Hirokazu Hasegawa, Takao KawasakiAbstract:Troglitazone, an oral antidiabetic agent, is an equal mixture of four stereoisomers involving two chiral centers. In the present study, the physical property of Troglitazone were investigated. The solid state of Troglitazone drug substance is characterized as a simple physical mixture of two diastereomers, as shown by the two endothermic peaks caused by the melting of the RR/SS and the RS/SR forms by differential scanning calorimetry (DSC). In addition, the powder X-ray diffraction pattern includes peaks resulting from both the RR/SS and the RS/SR forms. The water adsorption of Troglitazone drug substance is due to the presence of the RR/SS diastereomer, which adsorbs water as a monohydrate. The solubility of Troglitazone and the diastereomers were increased and the solubility ratios of the stereoisomers were changed by quenching. Troglitazone was proved to be stable against heat and humidity by the ratio of the stereoisomers and from the solid state form indicated by the DSC results.
