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

Abstract

This study investigates the impact of disease on nicotinic acid (NiAc)-induced changes in plasma concentrations of non-esterified fatty acids (NEFA). NiAc was given by constant intravenous infusion to normal Sprague-Dawley and obese Zucker rats, and arterial blood samples were taken for analysis of NiAc, NEFA, insulin and glucose plasma concentrations. The intravenous route was intentionally selected to avoid confounding processes, such as absorption, following extravascular administration. Data were analyzed using nonlinear mixed effects modeling (NONMEM, version VI). The disposition of NiAc in the normal rats was described by a two-compartment model with endogenous synthesis of NiAc and two parallel capacity-limited elimination processes. In the obese rats disposition was described by a one-compartment model with endogenous synthesis of NiAc and one capacity-limited elimination process. The plasma concentration of NiAc drove NEFA (R) turnover via an inhibitory drug-mechanism function acting on the formation of NEFA. 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. Differences in the pharmacodynamic response of the two strains included, in the obese animals, an increased NEFA baseline, diminished rebound and post-rebound oscillation, and a more pronounced slowly developing tolerance during the period of constant drug exposure. The feedback model captured the NiAc-induced changes in NEFA response in both the normal and obese rats. Differences in the parameter estimates between the obese and normal rats included, in the former group, increases in R 0 , k in and p by 44, 41 and 78 %, respectively, and decreases in k out and γ by 64 and 84 %, respectively. The estimates of k tol and IC 50 were similar in both groups. The NiAc-NEFA concentration-response relationship at equilibrium was substantially different in the two groups, being shifted upwards and to the right, and being shallower in the obese rats. The extent of such shifts is important, as they demonstrate the impact of disease at equilibrium and, if ignored, will lead to erroneous dose predictions and, in consequence, poorly designed studies. The proposed models are primarily aimed at screening and selecting candidates with the highest potential of becoming a viable drug in man.

Nicotinic acid timed to feeding reverses tissue lipid accumulation and improves glucose control in obese Zucker rats[S]

“…To test this, we compared a NiAc washout exposure that delayed the plasma NiAc decay toward in vivo IC 50 for FFA lowering by several hours versus abrupt termination. A specific step-down infusion protocol needed to produce this profile was identified with the aid of a previously developed model describing acute NiAc pharmacokinetics and FFA response (21). The step-down NiAc infusion rates were 88.9, 58.3, 43.7, 34.0, 24.3, 17.0, and 9.7 nmol/min/kg.…”

“…This absence of tissue lipid lowering may have reflected a failure to lower average FFA levels over the 24 h period due to a combination of FFA rebound and insufficient containment of tolerance. We speculated that abrupt infusion termination, in the context of NiAc's short plasma half-life [2 min in the rat (21)], may exacerbate the FFA rebound. Furthermore, our initial study was performed without timing NiAc exposure to the feeding/fasting periods.…”

“…We aimed at, and achieved, plateau plasma NiAc concentrations of 1 µM, based on the concentrationresponse relationship for FFA lowering, delivering a close-to-maximal FFA suppression in substance naive rats (21,33). It is important to have a sufficient but not excessive level of NiAc for two reasons.…”

Dosing profile profoundly influences nicotinic acid's ability to improve metabolic control in rats

“…The dose selection was based on the previously obtained relationship between FFA lowering and NiAc infusion rate in NiAc-naïve lean and obese rats ( 26 ). NiAc (pyridine-3-carboxylic acid; Sigma-Aldrich, St. Louis, MO) was dissolved in sterile water and adjusted to physiological pH using sodium hydroxide.…”

“…2 ). This exposure level was selected based on previous data showing near maximal FFA suppression in NiAc-naïve Sprague Dawley rats ( 26 ). Plasma NiAc concentrations declined rapidly across all dosed groups during the postinfusion period.…”