Effects of Thymoquinone on the Pharmacokinetics and Pharmacodynamics of Glibenclamide in a Rat Model.

Glibenclamide and thymoquinone plasma concentrations were analysed using a sensitive RP-HPLC method, and non-compartmental model pharmacokinetic parameters were calculated. The maximum reduction in blood glucose level was observed 3 hours following glibenclamide administration, which reached 47.4% of baseline, whereas it was reduced by 53.0% to 56.2% when co-administrated with thymoquinone. Plasma concentration of glibenclamide was increased by 13.4% and 21.8% by the co-administration of thymoquinone as single and multiple doses, respectively (P<0.05). The AUC and TI/2 of glibenclamide were also increased respectively by 32.0% and 17.4% with a thymoquinone single dose, and by 52.5% and 92.8% after chronic treatment. Furthermore, diabetic rats treated with thymoquinone demonstrated a marked decrease in hepatic protein expressions of CYP3A2 and CYP2C 11 enzymes that are responsible for the metabolism of glibenclamide. The current data suggest that thymoquinone exhibits a synergistic effect with glibenclamide on glucose level, which could be explained by reducing CYP450 activity at the protein level.

Disposition of abouthiouzine: a novel antihyperthyroid drug.

Abouthiouzine is a novel antithyroid agent with a profile of fewer reported adverse effects than other currently used drugs. The purpose of this current work was to explore, for the first time, the disposition of abouthiouzine following intravenous and oral administration using an animal model; also, to study its plasma protein binding properties. Abouthiouzine (2 mg/kg intravenously) was administered to healthy male Vole rabbits and Beagle dogs. A dose of 20 mg/kg of the drug was also given orally to another group of Beagle dogs. Abouthiouzine plasma concentrations were measured using an HPLC method, and its pharmacokinetic parameters were determined by non-compartmental analysis. Abouthiouzine plasma protein binding was determined using an ultrafiltration technique. The drug was quickly eliminated from the rabbit and dog systemic circulations with terminal half-lives (T(1/2 lambda)) of 0.7 h and 1.9 h, respectively. The calculated T(1/2 lambda) following the oral administration in dogs was 1.8 h. Total abouthiouzine clearance (CL) in rabbits was 7.84+/-0.87 ml/min/kg, and 4.03+/-0.83 ml/min/kg in dogs. The apparent volume of distribution at steady state (V(ss)) in rabbits and dogs was 360.09+/-63.41 ml/kg and 481.10+/-62.64 ml/kg, respectively. The absolute oral bioavailability in dogs was approximately 16%, which may indicate poor absorption characteristics of the pure drug and/or an extensive first past effect. Protein binding studies have demonstrated that abouthiouzine has moderate-to-high binding properties ( approximately 63%-86%). Further studies are needed to evaluate the route of elimination of abouthiouzine in these animal models including any metabolite formation and the role of enterohepatic recycling in this process.

Pharmacokinetics of diclofenac in sheep following intravenous and intramuscular administration.

OBJECTIVES: The aim of this work was to examine the pharmacokinetics of diclofenac (DCLF) in sheep after intravenous (IV) and intramuscular (IM) dosing. ANIMALS: Healthy male Najdi sheep. MATERIALS AND METHODS: Diclofenac (1 mg kg(-1)) was administered to ten clinically healthy-male Najdi sheep IV or IM (n = 5 each). Blood samples (5 mL) were collected and serum was separated for drug analysis by high-performance liquid chromatography with UV detection. Diclofenac pharmacokinetic parameters were determined by noncompartmental analysis. RESULTS: Diclofenac is quickly eliminated from sheep with a terminal T(1/2lambda) of 2-3 hours for both routes of administration. Total DCLF clearance after IV and IM administration was 87.86 +/- 24.10 and 85.69 +/- 40.76 mL kg(-1) hour(-1) respectively. The absolute bioavailability of IM DCLF appears to be approximately 100%. CONCLUSIONS AND CLINICAL RELEVANCE: The drug should be administered two to three times daily in sheep by IM or IV injection to maintain therapeutic concentrations. Additional studies are needed to evaluate the route of elimination of DCLF in sheep including metabolites formation and the significance of enterohepatic circulation.

Liquid chromatographic assay of abouthiouzine in plasma and its application to pharmacokinetic studies.

Abouthiouzine is a newly synthesized antithyroid agent with a proposed less adverse effects profile than other currently used drugs. A simple and rapid reversed phase high performance liquid chromatography assay was developed to determine the concentration of abouthiouzine in human plasma. The procedure involved extraction of the drug and propranolol (internal standard) from the plasma using ethylacetate. The extract was evaporated under nitrogen and the residue was constituted with the mobile phase and injected onto micro-Bondapack phenyl column (10 microm, 3.9 mm x 150 mm). The mobile phase consisted of 10 mM potassium dihydrogen phosphate buffer, acetonitrile, and methanol in the ratio of 60:25:15 (v/v/v, pH=3.0), which was delivered at a rate of 1.5 ml/min. Abouthiouzine and the internal standard were monitored using UV detection at 240 nm; the run time was less than 5 min. The detection limit of abouthiouzine is 0.5 microg/ml. The within- and between-day coefficients of variation were less than 7%. Our method has been successfully used to measure abouthiouzine plasma concentrations in a rabbit model following an intravenous administration of the drug.