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1.  Pharmacokinetics of salsalate and salicylic acid in normal and diabetic rats 
The pharmacokinetics (PK) of salsalate (SS) and salicylic acid (SA) was assessed in normal Wistar and diabetic Goto-Kakizaki rats. Three PK studies were conducted: 1) PK of SA in normal rats after intravenous dosing of SA at 20, 40, 80 mg/kg. 2) PK of SS and SA in normal rats after oral dosing of SS at 28, 56, 112 mg/kg. 3) PK during 4 months feeding of SS-containing diet in both normal and diabetic rats. The disposition of SS and SA were simultaneously evaluated using a pharmacokinetic model comprised of several transit absorption steps and linear and nonlinear dual elimination pathways for SA. The results indicated that the nonlinear elimination pathway of SA only accounted for a small fraction of the total clearance (< 12%) at therapeutic concentrations. A flat profile of SA was observed after oral dosing SS, particularly at a high dose. The possible reasons for this flat profile were posed. During the SS-diet feeding, diabetic rats achieved lower blood concentrations of SA than normal rats with a higher apparent clearance (CL/F) possibly due to incomplete (47%) bioavailability. Such CL/F decreased with age in both diabetic and normal rats. The effect of diabetes on SA pharmacokinetics may necessitate increased dosing in future usage of SS in diabetes.
doi:10.1002/bdd.1797
PMCID: PMC3440557  PMID: 22782506
salsalate; salicylic acid; pharmacokinetics; diabetes
2.  Mechanistic population modeling of diabetes disease progression in Goto-Kakizaki rat muscle 
Pyruvate dehydrogenase kinase 4 (PDK4) is a lipid status responsive gene involved in muscle fuel selection. Evidence is mounting in support of the therapeutic potential of PDK4 inhibitors to treat diabetes. Factors that regulate PDK4 mRNA expression include plasma corticosterone, insulin and free fatty acids. Our objective was to determine the impact of those plasma factors on PDK4 mRNA and to develop and validate a population mathematical model to differentiate aging, diet and disease effects on muscle PDK4 expression. The Goto-Kakizaki (GK) rat, a polygenic non-obese model of type 2 diabetes, was used as the diabetic animal model. We examined muscle PDK4 mRNA expression by real-time QRTPCR. Groups of GK rats along with controls fed with either a normal or high fat diet were sacrificed at 4, 8, 12, 16, and 20 weeks of age. Plasma corticosterone, insulin and free fatty acid were measured. The proposed mechanism-based model successfully described the age, disease and diet effects and the relative contribution of these plasma regulators on PDK4 mRNA expression. Muscle growth reduced the PDK4 mRNA production rate by 14% per gram increase. High fat diet increased the initial production rate constant in GK rats by 2.19-fold. The model indicated that corticosterone had a moderate effect and PDK4 was more sensitive to free fatty acid than insulin fluxes, which was in good agreement with the literature data.
doi:10.1002/bdd.738
PMCID: PMC3080028  PMID: 21162119
population model; type 2 diabetes; disease progression; PDK4; Goto-Kakizaki rats

Results 1-2 (2)