Physiologically based modeling of lisofylline pharmacokinetics following intravenous administration in mice

Lisofylline (LSF), is the R-(−) enantiomer of the metabolite M1 of pentoxifylline, and is currently under development for the treatment of type 1 diabetes. The aim of the study was to develop a physiologically based pharmacokinetic (PBPK) model of LSF in mice and to perform simulations in order to predict LSF concentrations in human serum and tissues following intravenous and oral administration. The concentrations of LSF in serum, brain, liver, kidneys, lungs, muscle, and gut were determined at different time points over 60 min by a chiral HPLC method with UV detection following a single intravenous dose of LSF to male CD-1 mice. A PBPK model was developed to describe serum pharmacokinetics and tissue distribution of LSF using ADAPT II software. All pharmacokinetic profiles were fitted simultaneously to obtain model parameters. The developed model characterized well LSF disposition in mice. The estimated intrinsic hepatic clearance was 5.427 ml/min and hepatic clearance calculated using the well-stirred model was 1.22 ml/min. The renal clearance of LSF was equal to zero. On scaling the model to humans, a good agreement was found between the predicted by the model and presented in literature serum LSF concentration–time profiles following an intravenous dose of 3 mg/kg. The predicted LSF concentrations in human tissues following oral administration were considerably lower despite the twofold higher dose used and may not be sufficient to exert a pharmacological effect. In conclusion, the mouse is a good model to study LSF pharmacokinetics following intravenous administration. The developed PBPK model may be useful to design future preclinical and clinical studies of this compound

Trace elements in glucometabolic disorders: an update

Many trace elements, among which metals, are indispensable for proper functioning of a myriad of biochemical reactions, more particularly as enzyme cofactors. This is particularly true for the vast set of processes involved in regulation of glucose homeostasis, being it in glucose metabolism itself or in hormonal control, especially insulin. The role and importance of trace elements such as chromium, zinc, selenium, lithium and vanadium are much less evident and subjected to chronic debate. This review updates our actual knowledge concerning these five trace elements. A careful survey of the literature shows that while theoretical postulates from some key roles of these elements had led to real hopes for therapy of insulin resistance and diabetes, the limited experience based on available data indicates that beneficial effects and use of most of them are subjected to caution, given the narrow window between safe and unsafe doses. Clear therapeutic benefit in these pathologies is presently doubtful but some data indicate that these metals may have a clinical interest in patients presenting deficiencies in individual metal levels. The same holds true for an association of some trace elements such as chromium or zinc with oral antidiabetics. However, this area is essentially unexplored in adequate clinical trials, which are worth being performed

Long-Term Exposure to [Cr3O(O2CCH2CH3)6(H2O)3]+ in Wistar Rats Fed Normal or High-Fat Diets Does Not Alter Glucose Metabolism

The essentiality of chromium(III) has been the subject of much debate, particularly in healthy subjects. Chromium(III)-containing supplements are widely used for body mass loss, building of lean muscle mass, and improving glucose and lipid metabolism. [Cr(3)O(O(2)CCH(2)CH(3))(6)(H(2)O)(3)](+), Cr3, is one of the most-studied chromium nutritional supplements. The current study evaluates the effects of long-term (15 months) supplementation with Cr3 on body mass and glucose metabolism in Wistar rats on traditional and cafeteria-style (high fat, high carbohydrate) diets. Male Wistar rats were randomly assigned to one of four treatment groups: 1) control diet (milled Harlan Teklad LM-485 rodent diet), 2) control diet + 1 mg Cr3/kg body mass/day, 3) a cafeteria-style (CAF) diet (high fat, high carbohydrate), or 4) CAF diet + 1 mg Cr3/kg/day. Cr3 supplementation had no effect on fasting blood glucose levels or blood glucose levels in response to glucose and insulin challenges. Rats consuming the CAF + Cr3 diet tended to have a significantly higher body mass than rats consuming the CAF diet, but necropsy results showed no difference in visceral fat or body wall thickness between groups. These data suggest that long-term Cr3 supplementation does not significantly affect body mass in rats consuming a normal diet or glucose levels or metabolism in rats consuming either diet

ICAM-1 and β2 Integrin Deficiency Impairs Fat Oxidation and Insulin Metabolism during Fasting

Intercellular adhesion molecule 1 (ICAM-1) and β2 integrins play critical roles in immune responses. ICAM-1 may also participate in regulation of energy balance because ICAM-1–deficient mice become obese on a high-fat diet. We show that mice deficient in these adhesion receptors are unable to respond to fasting by up-regulation of fatty acid oxidation. Normal mice, when fasted, exhibit reduced circulating neutrophil counts and increased ICAM-1 expression and neutrophil recruitment in liver. Mice lacking ICAM-1 or β2 integrins fail to show these responses—instead they become hypoglycemic with steatotic livers. Fasting ICAM-1–deficient mice reduce insulin more slowly than wild-type mice. This produces fasting hyperinsulinemia that prevents activation of adenosine mono-phosphate (AMP)-activated protein kinase in muscles and liver, which results in decreased import of long chain fatty acids into mitochondria. Thus, we show a new role for immune cells and their adhesion receptors in regulating metabolic response to fasting