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1.  Pharmacokinetics of Methylprednisolone after Intravenous and Intramuscular Administration in Rats 
Methylprednisolone (MPL) pharmacokinetics was examined in adrenalectomized (ADX) and normal rats to assess the feasibility of intramuscular (i.m.) dosing for use in pharmacodynamic studies. Several study phases were pursued. Parallel group studies were performed in normal and ADX rats given 50 mg/kg MPL (i.v. or i.m.) and blood samples were collected up to 6 h. Data from studies where normal rats were dosed with 50 mg/kg MPL i.m. and killed over either 6 or 96 h were combined to determine muscle site and plasma MPL concentrations. Lastly, ADX rats were dosed with 50 mg/kg MPL i.m. and killed over 18 h to assess hepatic tyrosine aminotransferase (TAT) dynamics. MPL exhibited bi-exponential kinetics after i.v. dosing with a terminal slope of 2.1 h−1. The i.m. drug was absorbed slowly with two first-order absorption rate constants, 1.26 and 0.219 h−1 indicating flip-flop kinetics with overall 50% bioavailability. The kinetics of MPL at the injection site exhibited slow, dual absorption rates. Although i.m. MPL showed lower bioavailability compared with other corticosteroids in rats, TAT dynamics revealed similar i.m. and i.v. response profiles. The more convenient intramuscular dosing can replace the i.v. route without causing marked differences in pharmacodynamics.
doi:10.1002/bdd.551
PMCID: PMC4181331  PMID: 17569107
methylprednisolone; corticosteroids; pharmacokinetics; intramuscular injection; tyrosine aminotransferase
2.  Pharmacokinetics, pharmacodynamics, and toxicities of methotrexate in healthy and collagen-induced arthritic rats 
Biopharmaceutics & drug disposition  2013;34(4):10.1002/bdd.1838.
Methotrexate (MTX) is an anchor drug used to treat rheumatoid arthritis (RA), but responsiveness is variable in effectiveness and toxicity. Methotrexate and its polyglutamate conjugates (MTXPGn) in red blood cells (RBC) have been associated with patient response. In the current study, 13 collagen-induced arthritic (CIA) rats and 12 healthy rats were given subcutaneous doses of either saline or 0.3 or 1.5 mg/kg per 2 days of MTX from day 21 to 43 post-induction. Blood samples were obtained at various times to measure MTX in plasma, and MTX and MTXPGn in RBC. Effects on disease progression were indicated by body weight and paw size. After multiple-doses, RBC MTX reached steady-state (82.4 nM) within 4 days. The MTXPG2 and MTXPG3 in RBC kept increasing until the end of the study attaining 12.5 and 17.7 nM. Significant weight loss was observed after dosing of 1.5 mg/kg/2 days, whereas moderate effectiveness was observed after dosing of 0.3 mg/kg/2 days. A pharmacokinetic/ pharmacodynamic/disease (PK/PD/DIS) model with indirect mechanisms and transduction components incorporating plasma MTX, RBC MTX, and RBC MTXPGn concentrations, and paw size was developed using naïve data pooling and ADAPT 5. The PK/PD in CIA rats dosed at 0.3 mg/kg/2 days were captured well by our proposed model. MTX showed modest (Imaxd = 0.16) but sensitive (IC50d = 0.712 nM) effectiveness on paw edema. The higher dose produced toxicity. The proposed model offers improved understanding of MTX effects on rheumatoid arthritis.
doi:10.1002/bdd.1838
PMCID: PMC3656137  PMID: 23456770
Methotrexate; rheumatoid arthritis; pharmacokinetics; pharmacodynamics; disease progression
3.  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
4.  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

Results 1-4 (4)