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Feedback modeling of non-esterified fatty acids in rats after nicotinic acid infusions.

Ahlström C, Peletier LA, Jansson-Löfmark R, Gabrielsson J - J Pharmacokinet Pharmacodyn (2010)

Bottom Line: Data were analyzed using nonlinear mixed effects modeling (NONMEM).This model can be used to provide information about factors that determine the time-course of NEFA response following different modes, rates and routes of administration of NiAc.The proposed model may also serve as a preclinical tool for analyzing and simulating drug-induced changes in plasma NEFA concentrations after treatment with NiAc or NiAc analogues.

View Article: PubMed Central - PubMed

Affiliation: Discovery DMPK and BAC, AstraZeneca R&D Mölndal, Mölndal, Sweden. Christine.Ahlstrom@pharm.gu.se

ABSTRACT
A feedback model was developed to describe the tolerance and oscillatory rebound seen in non-esterified fatty acid (NEFA) plasma concentrations following intravenous infusions of nicotinic acid (NiAc) to male Sprague-Dawley rats. NiAc was administered as an intravenous infusion over 30 min (0, 1, 5 or 20 μmol kg(-1) of body weight) or over 300 min (0, 5, 10 or 51 μmol kg(-1) of body weight), to healthy rats (n = 63), and serial arterial blood samples were taken for measurement of NiAc and NEFA plasma concentrations. Data were analyzed using nonlinear mixed effects modeling (NONMEM). The disposition of NiAc was described by a two-compartment model with endogenous turnover rate and two parallel capacity-limited elimination processes. The plasma concentration of NiAc was driving NEFA (R) turnover via an inhibitory drug-mechanism function acting on the formation of NEFA. The NEFA turnover was described by a feedback model with a moderator distributed over a series of transit compartments, where the first compartment (M (1)) inhibited the formation of R and the last compartment (M ( N )) stimulated the loss of R. All processes regulating plasma NEFA concentrations were assumed to be captured by the moderator function. The potency, IC (50), of NiAc was 45 nmol L(-1), the fractional turnover rate k ( out ) was 0.41 L mmol(-1) min(-1) and the turnover rate of moderator k ( tol ) was 0.027 min(-1). A lower physiological limit of NEFA was modeled as a NiAc-independent release (k ( cap )) of NEFA into plasma and was estimated to 0.032 mmol L(-1) min(-1). This model can be used to provide information about factors that determine the time-course of NEFA response following different modes, rates and routes of administration of NiAc. The proposed model may also serve as a preclinical tool for analyzing and simulating drug-induced changes in plasma NEFA concentrations after treatment with NiAc or NiAc analogues.

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Representative model fits of NiAc plasma concentration-time data at different durations (30 min (left) and 300 min (right)) and rates of NiAc infusion. Solid and dashed lines represents individual and population fits, respectively. Infusion started at time t = 0 min. Plots of all individual regressions are available from the author upon request
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Fig4: Representative model fits of NiAc plasma concentration-time data at different durations (30 min (left) and 300 min (right)) and rates of NiAc infusion. Solid and dashed lines represents individual and population fits, respectively. Infusion started at time t = 0 min. Plots of all individual regressions are available from the author upon request

Mentions: The endogenous synthesis of NiAc (Synt) was estimated to 0.0346 μmol min−1 kg−1 and the endogenous NiAc concentration, calculated according to Eq. 12 in Appendix A, was estimated to 6.8 nmol L−1. The shrinkage values were 27% for Vmax2, 46% for Cld and 48% for Synt. The final NiAc disposition parameter estimates, interindividual variability and their relative standard error (RSE) are shown in Table 1. The two-compartment turnover model (Fig. 1) described the experimental data on an individual bases in a consistent manner (see Fig. 4). The diagnostic plots in Fig. 5 confirmed the consistency of experimental and predicted NiAc concentrations and there were no marked trends in the residual plots.Table 1


Feedback modeling of non-esterified fatty acids in rats after nicotinic acid infusions.

Ahlström C, Peletier LA, Jansson-Löfmark R, Gabrielsson J - J Pharmacokinet Pharmacodyn (2010)

Representative model fits of NiAc plasma concentration-time data at different durations (30 min (left) and 300 min (right)) and rates of NiAc infusion. Solid and dashed lines represents individual and population fits, respectively. Infusion started at time t = 0 min. Plots of all individual regressions are available from the author upon request
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3020290&req=5

Fig4: Representative model fits of NiAc plasma concentration-time data at different durations (30 min (left) and 300 min (right)) and rates of NiAc infusion. Solid and dashed lines represents individual and population fits, respectively. Infusion started at time t = 0 min. Plots of all individual regressions are available from the author upon request
Mentions: The endogenous synthesis of NiAc (Synt) was estimated to 0.0346 μmol min−1 kg−1 and the endogenous NiAc concentration, calculated according to Eq. 12 in Appendix A, was estimated to 6.8 nmol L−1. The shrinkage values were 27% for Vmax2, 46% for Cld and 48% for Synt. The final NiAc disposition parameter estimates, interindividual variability and their relative standard error (RSE) are shown in Table 1. The two-compartment turnover model (Fig. 1) described the experimental data on an individual bases in a consistent manner (see Fig. 4). The diagnostic plots in Fig. 5 confirmed the consistency of experimental and predicted NiAc concentrations and there were no marked trends in the residual plots.Table 1

Bottom Line: Data were analyzed using nonlinear mixed effects modeling (NONMEM).This model can be used to provide information about factors that determine the time-course of NEFA response following different modes, rates and routes of administration of NiAc.The proposed model may also serve as a preclinical tool for analyzing and simulating drug-induced changes in plasma NEFA concentrations after treatment with NiAc or NiAc analogues.

View Article: PubMed Central - PubMed

Affiliation: Discovery DMPK and BAC, AstraZeneca R&D Mölndal, Mölndal, Sweden. Christine.Ahlstrom@pharm.gu.se

ABSTRACT
A feedback model was developed to describe the tolerance and oscillatory rebound seen in non-esterified fatty acid (NEFA) plasma concentrations following intravenous infusions of nicotinic acid (NiAc) to male Sprague-Dawley rats. NiAc was administered as an intravenous infusion over 30 min (0, 1, 5 or 20 μmol kg(-1) of body weight) or over 300 min (0, 5, 10 or 51 μmol kg(-1) of body weight), to healthy rats (n = 63), and serial arterial blood samples were taken for measurement of NiAc and NEFA plasma concentrations. Data were analyzed using nonlinear mixed effects modeling (NONMEM). The disposition of NiAc was described by a two-compartment model with endogenous turnover rate and two parallel capacity-limited elimination processes. The plasma concentration of NiAc was driving NEFA (R) turnover via an inhibitory drug-mechanism function acting on the formation of NEFA. The NEFA turnover was described by a feedback model with a moderator distributed over a series of transit compartments, where the first compartment (M (1)) inhibited the formation of R and the last compartment (M ( N )) stimulated the loss of R. All processes regulating plasma NEFA concentrations were assumed to be captured by the moderator function. The potency, IC (50), of NiAc was 45 nmol L(-1), the fractional turnover rate k ( out ) was 0.41 L mmol(-1) min(-1) and the turnover rate of moderator k ( tol ) was 0.027 min(-1). A lower physiological limit of NEFA was modeled as a NiAc-independent release (k ( cap )) of NEFA into plasma and was estimated to 0.032 mmol L(-1) min(-1). This model can be used to provide information about factors that determine the time-course of NEFA response following different modes, rates and routes of administration of NiAc. The proposed model may also serve as a preclinical tool for analyzing and simulating drug-induced changes in plasma NEFA concentrations after treatment with NiAc or NiAc analogues.

Show MeSH
Related in: MedlinePlus