title: 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 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 [Formula: see text] 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 [Formula: see text], 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 [Formula: see text]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.
authors.affiliation: School of Engineering, University of Warwick, Coventry, UK. r.k.andersson@warwick.ac.uk.|Fraunhofer-Chalmers Centre, Chalmers Science Park, Gothenburg, Sweden. r.k.andersson@warwick.ac.uk.
authors.forename: Robert
authors.identifier: 0000-0002-0332-644X
authors.initials: R
authors.lastname: Andersson
authors.affiliation: iMED CVMD Bioscience Diabetes, AstraZeneca, Gothenburg, Sweden.|Division of Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agriculture Sciences, Uppsala, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Kroon
authors.affiliation: Fraunhofer-Chalmers Centre, Chalmers Science Park, Gothenburg, Sweden.|Systems and Synthetic Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
authors.forename: Joachim
authors.initials: J
authors.lastname: Almquist
authors.affiliation: Fraunhofer-Chalmers Centre, Chalmers Science Park, Gothenburg, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Jirstrand
authors.affiliation: iMED CVMD Bioscience Diabetes, AstraZeneca, Gothenburg, Sweden.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Oakes
authors.affiliation: School of Engineering, University of Warwick, Coventry, UK.
authors.forename: Neil D
authors.initials: ND
authors.lastname: Evans
authors.affiliation: School of Engineering, University of Warwick, Coventry, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Chappel
authors.affiliation: Division of Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agriculture Sciences, Uppsala, Sweden. johan.gabrielsson@slu.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Gabrielsson
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008954:Models, Biological; D009525:Niacin / Q000494:pharmacology*; D009765:Obesity / Q000097:blood* / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker
chemical_list: D005230:Fatty Acids, Nonesterified; D007328:Insulin; D009525:Niacin
keywords: Disease modeling; Dosing regimen; Meta-analysis; Nonlinear mixed-effects (NLME); Tolerance; Turnover models