The intravenous, intramuscular and oral pharmacokinetics of ibuprofen in broiler chickens were investigated. In a preliminary study, plasma ibuprofen concentration-time profiles, following i.v. (25 mg/kg) dosing were best described by a 2-compartment model. After intravenous administration, the volume of distribution at steady-state (Vd(ss)), the total systemic clearance (ClB), the elimination half-life (t1/2 beta) and the MRT were 0.303 L/kg, 482.3 ml/h.kg, 2.71 h and 1.02 h, respectively. After intramuscular administration of ibuprofen, the tmax and Cmax were 0.37 h, and 42.2 micrograms/mL, respectively, with an estimated bioavailability of 46.7%. After oral administration of ibuprofen, the tmax and Cmax were 0.31 h and 23.91 micrograms/mL, respectively, with an estimated bioavailability of 24.2%. This is a preliminary study, examining the use of ibuprofen in broiler chickens, and should be followed by tissue residue and efficacy studies in different disease states.

Key Words: 7-Benzyl-3-thia-7-azabicyclo[3.3. llnonane hydroperchlorate-class Ib antiarrhythmic agents.The Cardiac Arrhythmias Suppression Trial (CAST) was a recent placebo-controlled, randomized study designed to test the hypothesis that pharmacological suppression of asymptomatic or mildly symptomatic ectopic activity with class I agents would prevent lethal ventricular arrhythmias (18,42,43) during the first few months following myocardial infraction. The failure of class I antiarrhythmic drugs to reduce mortality (and the surprising finding of an increased incidence of sudden death for class Ic agents) caused the premature termination of CAST, thereby mandating a critical reexamination of the adequacy of existing pharmacological therapies for the suppression of ventricular arrhythmias. Presently, there are no antiarrhythmic agents possessing both a high efficacy for the suppression of potentially lethal ventricular arrhythmias and a low incidence of serious side effects (33,5334). Therefore, the development and therapeutic application of antiarrhythmic agents with specificity of action and tolerable systemic toxicity is a continuing challenge.In the last decade, 3,7-diheterabicyclo[3.3. llnonane (DHBCN) derivatives have been shown to possess potentially useful antiarrhythmic properties (26,28,55). Sparteine was the first compound of this family of heterocycles found to have class I antiarrhythmic activity (41). However, serious toxic effects such as nervousness, convulsions, and loss of muscular control limited its utility (34). Since that time, structure-activity relationships of a few bispidines [3,7-diazabicyclo[3.3. llnonane (28) which is a fragment from the inner ring system of the sparteine moiety] have been carefully examined (4,5,23,45,48, 5 1,56,57). Synthetic methodology to obtain a series DHBCN derivatives (4,5,23,56,57, Garrison GL, et al. Unpublished results) utilized a Mannich reaction. Selected derivatives ~~

The metabolism of BRB-I-28 (7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane), a novel class Ib antiarrhythmic agent, was characterized in vivo in dogs and rats and in vitro with rat liver microsomal preparations containing a NADPH-generating system. In dogs, rats and the in vitro hepatic microsomal oxidation system, BRB-I-28 was extensively metabolized to form 7-benzyl-3-thia-7-azabicyclo [3.3.1]nonane-3-oxide (I), a major metabolite. The metabolite I was produced via S-oxidation, presumably by the hepatic P-450 system. Formation of minor metabolite, 7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane (II) via the oxidation of the benzylic site was also identified in rats. Following intravenous and oral administration of BRB-I-28 to dogs, the plasma concentration of major metabolite I could be test described by a 1-compartmental model. The plasma AUC of metabolite I was 20% (i.v.) and 179.4% (oral) of that of the parent BRB-I-28, respectively, suggesting that BRB-I-28 was metabolized significantly by the first pass effect following oral administration. Extensive metabolism of BRB-I-28 to form metabolites I and II, which have demonstrated much lower antiarrhythmic activities, further supports previously observed pharmacodynamic and pharmacokinetic findings.

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