Comparative pharmacokinetic studies of dyphylline and some dyphylline prodrugs Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/6m311s35x

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  • Dyphylline is an analog of theophylline and the latter is the most popular member of the methylxanthine family in use for the treatment of asthma. Although dyphylline is devoid of some problems associated with theophylline, a reported short half-life has made it's clinical usefulness limited. To avoid this problem a series of monoesters and corresponding diesters of dyphylline was synthesized to serve as prodrugs which will liberate dyphylline in a controlled manner after administration. Ester hydrolysis rates were measured in vitro in both human and rabbit plasma. Data generated from a selective HPLC assay show dipivaloyl dyphylline has the slowest rate of enzymatic hydrolysis in plasma of both. Due to the slower conversion and its relatively high partition coefficient properties, dipivaloyl dyphylline was chosen for first trial in rabbits to analyze prodrug effects in vivo. Constant intravenous infusion and oral administration were used to evaluate the pharmacokinetics of this prodrug. For comparison, dyphylline was also administered intravenously in rabbits and a complete pharmacokinetic analysis was performed. A nonlinear regression program,SIMPLEX,for pharmacokinetic analysis was employed for convenient control from a computer terminal. Results indicate dipivaloyl dyphylline was rapidly hydrolyzed to dyphylline. The apparent half-time for removal of dyphylline from blood following intravenous dipivaloyl dyphylline administration was prolonged 1.5 times compared to intravenous administration of dyphylline. The apparent half-time for removal of dyphylline following oral administration of the prodrug was prolonged 10 times. It is concluded that the prolongation of duration of dyphylline blood concentrations following intravenous prodrug administration is due to the slow hydrolysis of the ester to dyphylline in the presence of nonspecific esterase. The prolongation of blood concentrations of dyphylline following oral administration of the prodrug is probably due to slow and prolonged prodrug dissolution in the gastrointestinal tract. These characterestics of prodrugs of dyphylline may provide a stragedy for design of a more effective product.
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