Comparison of rat and dog models of vasodilatation and lipolysis for the calculation of a therapeutic index for GPR109A agonists

Carballo-Jane, Ester; Gerckens, Lynn S.; Luell, Silvi; Parlapiano, Allison S.; Wolff, Michael; Colletti, Steven L.; Tata, James R.; Taggart, Andrew K.P.; Waters, M. Gerard; Richman, Jeremy G.; McCann, Margaret E.; Forrest, Michael J.

doi:10.1016/j.vascn.2007.05.007

Cited by 13 publications

(30 citation statements)

References 28 publications

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“…Because this lower limit is seen following administration of other GPR109A agonists (e.g. acipimox [31]), it is suggested to be a system- rather than a drug-specific parameter, so replacing k cap with I max in the drug mechanism function (Eq. 2) would not be mechanistically correct.…”

Section: Discussionmentioning

confidence: 99%

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

Ahlström

Peletier

Jansson‐Löfmark

et al. 2010

J Pharmacokinet Pharmacodyn

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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 (M1) inhibited the formation of R and the last compartment (MN) stimulated the loss of R. All processes regulating plasma NEFA concentrations were assumed to be captured by the moderator function. The potency, IC50, of NiAc was 45 nmol L−1, the fractional turnover rate kout was 0.41 L mmol−1 min−1 and the turnover rate of moderator ktol was 0.027 min−1. A lower physiological limit of NEFA was modeled as a NiAc-independent release (kcap) 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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Section: Discussionmentioning

confidence: 99%

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

Ahlström

Peletier

Jansson‐Löfmark

et al. 2010

J Pharmacokinet Pharmacodyn

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“…In this study the addition of Acipimox in the cell media was used as a control to baseline conditions, as there theoretically should be no differences in PCa cell uptake of neither FDG or acetate in media with or without Acipimox. According to reports by Carballo-Jane et al [22], the concentration of Acipimox used in the cell media was set to 0.1 mM.…”

Section: Methodsmentioning

confidence: 99%

Influence of free fatty acids on glucose uptake in prostate cancer cells

Andersen

Divilov

Sevak

et al. 2014

Nuclear Medicine and Biology

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Introduction The study focuses on the interaction between glucose and free fatty acids (FFA) in malignant human prostate cancer cell lines by an in vitro observation of uptake of fluoro-2-deoxy-d-glucose (FDG) and acetate. Methods Human prostate cancer cell lines (PC3, CWR22Rv1, LNCaP, and DU145) were incubated for 2 h and 24 h in glucose-containing (5.5 mM) Dulbecco’s Modified Eagle’s Medium (DMEM) with varying concentrations of the free fatty acid palmitate (0–1.0 mM). Then the cells were incubated with [18 F]-FDG (1 µCi/mL; 0.037 MBq/mL) in DMEM either in presence or absence of glucose and in presence of varying concentrations of palmitate for 1 h. Standardized procedures regarding cell counting and measuring for 18F radioactivity were applied. Cell uptake studies with 14C-1-acetate under the same conditions were performed on PC3 cells. Results In glucose containing media there was significantly increased FDG uptake after 24 h incubation in all cell lines, except DU145, when upper physiological levels of palmitate were added. A 4-fold increase of FDG uptake in PC3 cells (15.11% vs. 3.94%/106 cells) was observed in media with 1.0 mM palmitate compared to media with no palmitate. The same tendency was observed in PC3 and CWR22Rv1 cells after 2 h incubation. In glucose-free media no significant differences in FDG uptake after 24 h incubation were observed. The significant differences after 2 h incubation all pointed in the direction of increased FDG uptake when palmitate was added. Acetate uptake in PC3 cells was significantly lower when palmitate was added in glucose-free DMEM. No clear tendency when comparing FDG or acetate uptake in the same media at different time points of incubation was observed. Conclusions Our results indicate a FFA dependent metabolic boost/switch of glucose uptake in PCa, with patterns reflecting the true heterogeneity of the disease.

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“…Since a single dose of niacin acutely reduces NEFA concentrations to a similar extent as short-term administration (4,26,34), we hypothesized that a single dose of niacin might also increase serum adiponectin concentrations. In the current investigation, total serum adiponectin concentrations increased by 37% within 10 min, peaked within 1 h, and remained elevated above baseline for Յ24 h (Fig.…”

Section: Niacin Acutely Increases Total Adiponectin Concentrations Anmentioning

confidence: 99%

Niacin stimulates adiponectin secretion through the GPR109A receptor

Plaisance

Lukasova²,

Offermanns³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

104

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Niacin (nicotinic acid) has recently been shown to increase serum adiponectin concentrations in men with the metabolic syndrome. However, little is known about the mechanism(s) by which niacin regulates the intracellular trafficking and secretion of adiponectin. Since niacin appears to exert its effects on lipolysis through receptor (GPR109A)-dependent and -independent pathways, the purpose of this investigation was to examine the role of the recently identified GPR109A receptor in adiponectin secretion. Initial in vivo studies in rats demonstrated that niacin (30 mg/kg po) acutely increases serum adiponectin concentrations, whereas it decreases NEFAs. Further in vitro studies demonstrated an increase in adiponectin secretion and a decrease in lipolysis in primary adipocytes following treatment with niacin or ␤-hydroxybutyrate (an endogenous ligand of the GPR109A receptor), but these effects were blocked when adipocytes were pretreated with pertussis toxin. Niacin had no effect on adiponectin secretion or lipolysis in 3T3-L1 adipocytes, which have limited cell surface expression of the GPR109A receptor. To further substantiate these in vitro findings, wild-type and GPR109A receptor knockout mice were administered a single dose of niacin or placebo, and serum was obtained for the determination of adiponectin and NEFA concentrations. Serum adiponectin concentrations increased and serum NEFAs decreased in the wild-type mice within 10 min following niacin administration. However, niacin administration had no effect on adiponectin and NEFA concentrations in the GPR109A receptor knockout mice. These results demonstrate that the GPR109A receptor plays an important role in the dual regulation of adiponectin secretion and lipolysis. nicotinic acid; PUMA-G; HM74A; nonesterified fatty acids; lipolysis NIACIN (NICOTINIC ACID) HAS BEEN USED for more than 50 years as a pharmacological agent for the treatment of dyslipidemia and remains an effective strategy to decrease serum triglycerides and increase HDL cholesterol concentrations (6,19). In one of the first randomized clinical trials of heart disease prevention, niacin reduced serum triglyceride concentrations by 27% and nonfatal myocardial infarctions and cardiovascular disease (CVD) mortality by 27 and 26%, respectively (6a). More recent studies provide evidence that niacin is associated with a reduction in the number of angiographically documented vascular lesions and carotid artery intima-media thickness in patients with CVD (16, 31).The cardioprotective benefits of niacin have been attributed primarily to improvements in blood lipid and lipoprotein characteristics and reductions in vascular inflammation and thrombosis (18). However, recent studies have demonstrated that niacin significantly modulates serum adipokine concentrations. Westphal et al. (36) demonstrated that 6 wk of niacin treatment increased serum adiponectin concentrations by 54% in obese men with the metabolic syndrome. Investigations from our laboratory support these findings and further demonstrate th...

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Comparison of rat and dog models of vasodilatation and lipolysis for the calculation of a therapeutic index for GPR109A agonists

Cited by 13 publications

References 28 publications

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

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

Influence of free fatty acids on glucose uptake in prostate cancer cells

Niacin stimulates adiponectin secretion through the GPR109A receptor

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