Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments

AbstractNicotinic 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–Dawle y 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\({\upmu {\text{M}}}\), respectively, in obese rats. A range of dosing regimens was analyzed and predictions made for optimizing NiAc delivery to minimize FFA expos...
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research