Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments
Abstract Nicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis. Acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. Sustained NiAc exposure is associated with tolerance development (drug resistance) and complete adaptation (FFA returnin...
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| Autor*in: |
Andersson, Robert [verfasserIn] Kroon, Tobias [verfasserIn] Almquist, Joachim [verfasserIn] Jirstrand, Mats [verfasserIn] Oakes, Nicholas D. [verfasserIn] Evans, Neil D. [verfasserIn] Chappel, Michael J. [verfasserIn] Gabrielsson, Johan [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2017 |
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| Übergeordnetes Werk: |
Enthalten in: Journal of Pharmacokinetics and Biopharmaceutics - Kluwer Academic Publishers-Plenum Publishers, 1973, 44(2017), 3 vom: 21. Feb., Seite 203-222 |
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| Übergeordnetes Werk: |
volume:44 ; year:2017 ; number:3 ; day:21 ; month:02 ; pages:203-222 |
| Links: |
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| DOI / URN: |
10.1007/s10928-017-9512-6 |
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| Katalog-ID: |
SPR014713012 |
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| 245 | 1 | 0 | |a Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments |
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| 520 | |a Abstract Nicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis. Acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. Sustained NiAc exposure is associated with tolerance development (drug resistance) and complete adaptation (FFA returning to pretreatment levels). We conducted a meta-analysis on a rich pre-clinical data set of the NiAc–FFA interaction to establish the acute and chronic exposure-response relations from a macro perspective. The data were analyzed using a nonlinear mixed-effects framework. We also developed a new turnover model that describes the adaptation seen in plasma FFA concentrations in lean Sprague–Dawley and obese Zucker rats following acute and chronic NiAc exposure. The adaptive mechanisms within the system were described using integral control systems and dynamic efficacies in the traditional %$I_{\text{max}}%$ model. Insulin was incorporated in parallel with NiAc as the main endogenous co-variate of FFA dynamics. The model captured profound insulin resistance and complete drug resistance in obese rats. The efficacy of NiAc as an inhibitor of FFA release went from 1 to approximately 0 during sustained exposure in obese rats. The potency of NiAc as an inhibitor of insulin and of FFA release was estimated to be 0.338 and 0.436 %${\mu {\text{M}}}%$, respectively, in obese rats. A range of dosing regimens was analyzed and predictions made for optimizing NiAc delivery to minimize FFA exposure. Given the exposure levels of the experiments, the importance of washout periods in-between NiAc infusions was illustrated. The washout periods should be %$\sim%$2 h longer than the infusions in order to optimize 24 h lowering of FFA in rats. However, the predicted concentration-response relationships suggests that higher AUC reductions might be attained at lower NiAc exposures. | ||
| 650 | 4 | |a Meta-analysis |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Turnover models |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Nonlinear mixed-effects (NLME) |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Tolerance |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Disease modeling |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Dosing regimen |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Kroon, Tobias |e verfasserin |4 aut | |
| 700 | 1 | |a Almquist, Joachim |e verfasserin |4 aut | |
| 700 | 1 | |a Jirstrand, Mats |e verfasserin |4 aut | |
| 700 | 1 | |a Oakes, Nicholas D. |e verfasserin |4 aut | |
| 700 | 1 | |a Evans, Neil D. |e verfasserin |4 aut | |
| 700 | 1 | |a Chappel, Michael J. |e verfasserin |4 aut | |
| 700 | 1 | |a Gabrielsson, Johan |e verfasserin |4 aut | |
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10.1007/s10928-017-9512-6 doi (DE-627)SPR014713012 (SPR)s10928-017-9512-6-e DE-627 ger DE-627 rakwb eng Andersson, Robert verfasserin aut Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Nicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis. Acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. Sustained NiAc exposure is associated with tolerance development (drug resistance) and complete adaptation (FFA returning to pretreatment levels). We conducted a meta-analysis on a rich pre-clinical data set of the NiAc–FFA interaction to establish the acute and chronic exposure-response relations from a macro perspective. The data were analyzed using a nonlinear mixed-effects framework. We also developed a new turnover model that describes the adaptation seen in plasma FFA concentrations in lean Sprague–Dawley and obese Zucker rats following acute and chronic NiAc exposure. The adaptive mechanisms within the system were described using integral control systems and dynamic efficacies in the traditional %$I_{\text{max}}%$ model. Insulin was incorporated in parallel with NiAc as the main endogenous co-variate of FFA dynamics. The model captured profound insulin resistance and complete drug resistance in obese rats. The efficacy of NiAc as an inhibitor of FFA release went from 1 to approximately 0 during sustained exposure in obese rats. The potency of NiAc as an inhibitor of insulin and of FFA release was estimated to be 0.338 and 0.436 %${\mu {\text{M}}}%$, respectively, in obese rats. A range of dosing regimens was analyzed and predictions made for optimizing NiAc delivery to minimize FFA exposure. Given the exposure levels of the experiments, the importance of washout periods in-between NiAc infusions was illustrated. The washout periods should be %$\sim%$2 h longer than the infusions in order to optimize 24 h lowering of FFA in rats. However, the predicted concentration-response relationships suggests that higher AUC reductions might be attained at lower NiAc exposures. Meta-analysis (dpeaa)DE-He213 Turnover models (dpeaa)DE-He213 Nonlinear mixed-effects (NLME) (dpeaa)DE-He213 Tolerance (dpeaa)DE-He213 Disease modeling (dpeaa)DE-He213 Dosing regimen (dpeaa)DE-He213 Kroon, Tobias verfasserin aut Almquist, Joachim verfasserin aut Jirstrand, Mats verfasserin aut Oakes, Nicholas D. verfasserin aut Evans, Neil D. verfasserin aut Chappel, Michael J. verfasserin aut Gabrielsson, Johan verfasserin aut Enthalten in Journal of Pharmacokinetics and Biopharmaceutics Kluwer Academic Publishers-Plenum Publishers, 1973 44(2017), 3 vom: 21. Feb., Seite 203-222 (DE-627)SPR014694166 nnns volume:44 year:2017 number:3 day:21 month:02 pages:203-222 https://dx.doi.org/10.1007/s10928-017-9512-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_40 AR 44 2017 3 21 02 203-222 |
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10.1007/s10928-017-9512-6 doi (DE-627)SPR014713012 (SPR)s10928-017-9512-6-e DE-627 ger DE-627 rakwb eng Andersson, Robert verfasserin aut Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Nicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis. Acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. Sustained NiAc exposure is associated with tolerance development (drug resistance) and complete adaptation (FFA returning to pretreatment levels). We conducted a meta-analysis on a rich pre-clinical data set of the NiAc–FFA interaction to establish the acute and chronic exposure-response relations from a macro perspective. The data were analyzed using a nonlinear mixed-effects framework. We also developed a new turnover model that describes the adaptation seen in plasma FFA concentrations in lean Sprague–Dawley and obese Zucker rats following acute and chronic NiAc exposure. The adaptive mechanisms within the system were described using integral control systems and dynamic efficacies in the traditional %$I_{\text{max}}%$ model. Insulin was incorporated in parallel with NiAc as the main endogenous co-variate of FFA dynamics. The model captured profound insulin resistance and complete drug resistance in obese rats. The efficacy of NiAc as an inhibitor of FFA release went from 1 to approximately 0 during sustained exposure in obese rats. The potency of NiAc as an inhibitor of insulin and of FFA release was estimated to be 0.338 and 0.436 %${\mu {\text{M}}}%$, respectively, in obese rats. A range of dosing regimens was analyzed and predictions made for optimizing NiAc delivery to minimize FFA exposure. Given the exposure levels of the experiments, the importance of washout periods in-between NiAc infusions was illustrated. The washout periods should be %$\sim%$2 h longer than the infusions in order to optimize 24 h lowering of FFA in rats. However, the predicted concentration-response relationships suggests that higher AUC reductions might be attained at lower NiAc exposures. Meta-analysis (dpeaa)DE-He213 Turnover models (dpeaa)DE-He213 Nonlinear mixed-effects (NLME) (dpeaa)DE-He213 Tolerance (dpeaa)DE-He213 Disease modeling (dpeaa)DE-He213 Dosing regimen (dpeaa)DE-He213 Kroon, Tobias verfasserin aut Almquist, Joachim verfasserin aut Jirstrand, Mats verfasserin aut Oakes, Nicholas D. verfasserin aut Evans, Neil D. verfasserin aut Chappel, Michael J. verfasserin aut Gabrielsson, Johan verfasserin aut Enthalten in Journal of Pharmacokinetics and Biopharmaceutics Kluwer Academic Publishers-Plenum Publishers, 1973 44(2017), 3 vom: 21. Feb., Seite 203-222 (DE-627)SPR014694166 nnns volume:44 year:2017 number:3 day:21 month:02 pages:203-222 https://dx.doi.org/10.1007/s10928-017-9512-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_40 AR 44 2017 3 21 02 203-222 |
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10.1007/s10928-017-9512-6 doi (DE-627)SPR014713012 (SPR)s10928-017-9512-6-e DE-627 ger DE-627 rakwb eng Andersson, Robert verfasserin aut Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Nicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis. Acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. Sustained NiAc exposure is associated with tolerance development (drug resistance) and complete adaptation (FFA returning to pretreatment levels). We conducted a meta-analysis on a rich pre-clinical data set of the NiAc–FFA interaction to establish the acute and chronic exposure-response relations from a macro perspective. The data were analyzed using a nonlinear mixed-effects framework. We also developed a new turnover model that describes the adaptation seen in plasma FFA concentrations in lean Sprague–Dawley and obese Zucker rats following acute and chronic NiAc exposure. The adaptive mechanisms within the system were described using integral control systems and dynamic efficacies in the traditional %$I_{\text{max}}%$ model. Insulin was incorporated in parallel with NiAc as the main endogenous co-variate of FFA dynamics. The model captured profound insulin resistance and complete drug resistance in obese rats. The efficacy of NiAc as an inhibitor of FFA release went from 1 to approximately 0 during sustained exposure in obese rats. The potency of NiAc as an inhibitor of insulin and of FFA release was estimated to be 0.338 and 0.436 %${\mu {\text{M}}}%$, respectively, in obese rats. A range of dosing regimens was analyzed and predictions made for optimizing NiAc delivery to minimize FFA exposure. Given the exposure levels of the experiments, the importance of washout periods in-between NiAc infusions was illustrated. The washout periods should be %$\sim%$2 h longer than the infusions in order to optimize 24 h lowering of FFA in rats. However, the predicted concentration-response relationships suggests that higher AUC reductions might be attained at lower NiAc exposures. Meta-analysis (dpeaa)DE-He213 Turnover models (dpeaa)DE-He213 Nonlinear mixed-effects (NLME) (dpeaa)DE-He213 Tolerance (dpeaa)DE-He213 Disease modeling (dpeaa)DE-He213 Dosing regimen (dpeaa)DE-He213 Kroon, Tobias verfasserin aut Almquist, Joachim verfasserin aut Jirstrand, Mats verfasserin aut Oakes, Nicholas D. verfasserin aut Evans, Neil D. verfasserin aut Chappel, Michael J. verfasserin aut Gabrielsson, Johan verfasserin aut Enthalten in Journal of Pharmacokinetics and Biopharmaceutics Kluwer Academic Publishers-Plenum Publishers, 1973 44(2017), 3 vom: 21. Feb., Seite 203-222 (DE-627)SPR014694166 nnns volume:44 year:2017 number:3 day:21 month:02 pages:203-222 https://dx.doi.org/10.1007/s10928-017-9512-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_40 AR 44 2017 3 21 02 203-222 |
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10.1007/s10928-017-9512-6 doi (DE-627)SPR014713012 (SPR)s10928-017-9512-6-e DE-627 ger DE-627 rakwb eng Andersson, Robert verfasserin aut Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Nicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis. Acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. Sustained NiAc exposure is associated with tolerance development (drug resistance) and complete adaptation (FFA returning to pretreatment levels). We conducted a meta-analysis on a rich pre-clinical data set of the NiAc–FFA interaction to establish the acute and chronic exposure-response relations from a macro perspective. The data were analyzed using a nonlinear mixed-effects framework. We also developed a new turnover model that describes the adaptation seen in plasma FFA concentrations in lean Sprague–Dawley and obese Zucker rats following acute and chronic NiAc exposure. The adaptive mechanisms within the system were described using integral control systems and dynamic efficacies in the traditional %$I_{\text{max}}%$ model. Insulin was incorporated in parallel with NiAc as the main endogenous co-variate of FFA dynamics. The model captured profound insulin resistance and complete drug resistance in obese rats. The efficacy of NiAc as an inhibitor of FFA release went from 1 to approximately 0 during sustained exposure in obese rats. The potency of NiAc as an inhibitor of insulin and of FFA release was estimated to be 0.338 and 0.436 %${\mu {\text{M}}}%$, respectively, in obese rats. A range of dosing regimens was analyzed and predictions made for optimizing NiAc delivery to minimize FFA exposure. Given the exposure levels of the experiments, the importance of washout periods in-between NiAc infusions was illustrated. The washout periods should be %$\sim%$2 h longer than the infusions in order to optimize 24 h lowering of FFA in rats. However, the predicted concentration-response relationships suggests that higher AUC reductions might be attained at lower NiAc exposures. Meta-analysis (dpeaa)DE-He213 Turnover models (dpeaa)DE-He213 Nonlinear mixed-effects (NLME) (dpeaa)DE-He213 Tolerance (dpeaa)DE-He213 Disease modeling (dpeaa)DE-He213 Dosing regimen (dpeaa)DE-He213 Kroon, Tobias verfasserin aut Almquist, Joachim verfasserin aut Jirstrand, Mats verfasserin aut Oakes, Nicholas D. verfasserin aut Evans, Neil D. verfasserin aut Chappel, Michael J. verfasserin aut Gabrielsson, Johan verfasserin aut Enthalten in Journal of Pharmacokinetics and Biopharmaceutics Kluwer Academic Publishers-Plenum Publishers, 1973 44(2017), 3 vom: 21. Feb., Seite 203-222 (DE-627)SPR014694166 nnns volume:44 year:2017 number:3 day:21 month:02 pages:203-222 https://dx.doi.org/10.1007/s10928-017-9512-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_40 AR 44 2017 3 21 02 203-222 |
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10.1007/s10928-017-9512-6 doi (DE-627)SPR014713012 (SPR)s10928-017-9512-6-e DE-627 ger DE-627 rakwb eng Andersson, Robert verfasserin aut Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Nicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis. Acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. Sustained NiAc exposure is associated with tolerance development (drug resistance) and complete adaptation (FFA returning to pretreatment levels). We conducted a meta-analysis on a rich pre-clinical data set of the NiAc–FFA interaction to establish the acute and chronic exposure-response relations from a macro perspective. The data were analyzed using a nonlinear mixed-effects framework. We also developed a new turnover model that describes the adaptation seen in plasma FFA concentrations in lean Sprague–Dawley and obese Zucker rats following acute and chronic NiAc exposure. The adaptive mechanisms within the system were described using integral control systems and dynamic efficacies in the traditional %$I_{\text{max}}%$ model. Insulin was incorporated in parallel with NiAc as the main endogenous co-variate of FFA dynamics. The model captured profound insulin resistance and complete drug resistance in obese rats. The efficacy of NiAc as an inhibitor of FFA release went from 1 to approximately 0 during sustained exposure in obese rats. The potency of NiAc as an inhibitor of insulin and of FFA release was estimated to be 0.338 and 0.436 %${\mu {\text{M}}}%$, respectively, in obese rats. A range of dosing regimens was analyzed and predictions made for optimizing NiAc delivery to minimize FFA exposure. Given the exposure levels of the experiments, the importance of washout periods in-between NiAc infusions was illustrated. The washout periods should be %$\sim%$2 h longer than the infusions in order to optimize 24 h lowering of FFA in rats. However, the predicted concentration-response relationships suggests that higher AUC reductions might be attained at lower NiAc exposures. Meta-analysis (dpeaa)DE-He213 Turnover models (dpeaa)DE-He213 Nonlinear mixed-effects (NLME) (dpeaa)DE-He213 Tolerance (dpeaa)DE-He213 Disease modeling (dpeaa)DE-He213 Dosing regimen (dpeaa)DE-He213 Kroon, Tobias verfasserin aut Almquist, Joachim verfasserin aut Jirstrand, Mats verfasserin aut Oakes, Nicholas D. verfasserin aut Evans, Neil D. verfasserin aut Chappel, Michael J. verfasserin aut Gabrielsson, Johan verfasserin aut Enthalten in Journal of Pharmacokinetics and Biopharmaceutics Kluwer Academic Publishers-Plenum Publishers, 1973 44(2017), 3 vom: 21. Feb., Seite 203-222 (DE-627)SPR014694166 nnns volume:44 year:2017 number:3 day:21 month:02 pages:203-222 https://dx.doi.org/10.1007/s10928-017-9512-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_40 AR 44 2017 3 21 02 203-222 |
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Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments Meta-analysis (dpeaa)DE-He213 Turnover models (dpeaa)DE-He213 Nonlinear mixed-effects (NLME) (dpeaa)DE-He213 Tolerance (dpeaa)DE-He213 Disease modeling (dpeaa)DE-He213 Dosing regimen (dpeaa)DE-He213 |
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modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments |
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Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments |
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Abstract Nicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis. Acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. Sustained NiAc exposure is associated with tolerance development (drug resistance) and complete adaptation (FFA returning to pretreatment levels). We conducted a meta-analysis on a rich pre-clinical data set of the NiAc–FFA interaction to establish the acute and chronic exposure-response relations from a macro perspective. The data were analyzed using a nonlinear mixed-effects framework. We also developed a new turnover model that describes the adaptation seen in plasma FFA concentrations in lean Sprague–Dawley and obese Zucker rats following acute and chronic NiAc exposure. The adaptive mechanisms within the system were described using integral control systems and dynamic efficacies in the traditional %$I_{\text{max}}%$ model. Insulin was incorporated in parallel with NiAc as the main endogenous co-variate of FFA dynamics. The model captured profound insulin resistance and complete drug resistance in obese rats. The efficacy of NiAc as an inhibitor of FFA release went from 1 to approximately 0 during sustained exposure in obese rats. The potency of NiAc as an inhibitor of insulin and of FFA release was estimated to be 0.338 and 0.436 %${\mu {\text{M}}}%$, respectively, in obese rats. A range of dosing regimens was analyzed and predictions made for optimizing NiAc delivery to minimize FFA exposure. Given the exposure levels of the experiments, the importance of washout periods in-between NiAc infusions was illustrated. The washout periods should be %$\sim%$2 h longer than the infusions in order to optimize 24 h lowering of FFA in rats. However, the predicted concentration-response relationships suggests that higher AUC reductions might be attained at lower NiAc exposures. |
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Abstract Nicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis. Acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. Sustained NiAc exposure is associated with tolerance development (drug resistance) and complete adaptation (FFA returning to pretreatment levels). We conducted a meta-analysis on a rich pre-clinical data set of the NiAc–FFA interaction to establish the acute and chronic exposure-response relations from a macro perspective. The data were analyzed using a nonlinear mixed-effects framework. We also developed a new turnover model that describes the adaptation seen in plasma FFA concentrations in lean Sprague–Dawley and obese Zucker rats following acute and chronic NiAc exposure. The adaptive mechanisms within the system were described using integral control systems and dynamic efficacies in the traditional %$I_{\text{max}}%$ model. Insulin was incorporated in parallel with NiAc as the main endogenous co-variate of FFA dynamics. The model captured profound insulin resistance and complete drug resistance in obese rats. The efficacy of NiAc as an inhibitor of FFA release went from 1 to approximately 0 during sustained exposure in obese rats. The potency of NiAc as an inhibitor of insulin and of FFA release was estimated to be 0.338 and 0.436 %${\mu {\text{M}}}%$, respectively, in obese rats. A range of dosing regimens was analyzed and predictions made for optimizing NiAc delivery to minimize FFA exposure. Given the exposure levels of the experiments, the importance of washout periods in-between NiAc infusions was illustrated. The washout periods should be %$\sim%$2 h longer than the infusions in order to optimize 24 h lowering of FFA in rats. However, the predicted concentration-response relationships suggests that higher AUC reductions might be attained at lower NiAc exposures. |
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Abstract Nicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis. Acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. Sustained NiAc exposure is associated with tolerance development (drug resistance) and complete adaptation (FFA returning to pretreatment levels). We conducted a meta-analysis on a rich pre-clinical data set of the NiAc–FFA interaction to establish the acute and chronic exposure-response relations from a macro perspective. The data were analyzed using a nonlinear mixed-effects framework. We also developed a new turnover model that describes the adaptation seen in plasma FFA concentrations in lean Sprague–Dawley and obese Zucker rats following acute and chronic NiAc exposure. The adaptive mechanisms within the system were described using integral control systems and dynamic efficacies in the traditional %$I_{\text{max}}%$ model. Insulin was incorporated in parallel with NiAc as the main endogenous co-variate of FFA dynamics. The model captured profound insulin resistance and complete drug resistance in obese rats. The efficacy of NiAc as an inhibitor of FFA release went from 1 to approximately 0 during sustained exposure in obese rats. The potency of NiAc as an inhibitor of insulin and of FFA release was estimated to be 0.338 and 0.436 %${\mu {\text{M}}}%$, respectively, in obese rats. A range of dosing regimens was analyzed and predictions made for optimizing NiAc delivery to minimize FFA exposure. Given the exposure levels of the experiments, the importance of washout periods in-between NiAc infusions was illustrated. The washout periods should be %$\sim%$2 h longer than the infusions in order to optimize 24 h lowering of FFA in rats. However, the predicted concentration-response relationships suggests that higher AUC reductions might be attained at lower NiAc exposures. |
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