Feedback modeling of non-esterified fatty acids in rats after nicotinic acid infusions.
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.
Discovery DMPK and BAC, AstraZeneca R&D Mölndal, Mölndal, Sweden. Christine.Ahlstrom@pharm.gu.se
Christine
C
Ahlström
Lambertus A
LA
Peletier
Rasmus
R
Jansson-Löfmark
Johan
J
Gabrielsson
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D025461:Feedback, Physiological; D008658:Inactivation, Metabolic; D007262:Infusions, Intravenous; D008297:Male; D008954:Models, Biological; D009525:Niacin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014803:Vitamin B Complex / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
D005230:Fatty Acids, Nonesterified; D014803:Vitamin B Complex; D009525:Niacin