Graduate Thesis Or Dissertation
 

The absolute bioavailability of dyphylline tablets in human subjects

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  • Dyphylline has been shown to be rapidly and completely absorbed from oral tablets in an absolute bioavailability study. In a pilot study two healthy male subjects received 1000 mg of dyphylline via intravenous infuson at a rate of 50 mg/min (1.0 ml/min) for 20 minutes. Plasma samples were collected for 16 hours and urine samples were collected for 72 hours. Observed peak plasma concentration were 22.4 mcg/ml for subject one and 25.7 mcg/ml for subject two. No adverse effects were reported by either subject; blood pressure and pulse rate remained normal. An average of 83% of the administered dose of dyphylline was recovered in the urine. The remaining 17% of the dose may be distributed to "deep tissues" and removed slowly. Computer based pharmacokinetic modeling of the plasma data, 0-8 hours for subject one and 0-7 hours for subject two, were best described by a two compartment open model with first order elimination from the central compartment. However, sigma-minus plots of time extended urine data reveal nonlinear or multicompartmental pharmacokinetics. Evidence from the pilot study revealed that intravenous dyphylline can be safely administered to human subjects at the given dose and rate infused. Also, pharmacokinetic data from the pilot study provided background information to proceed with a twelve subject study of the absolute bioavailability of dyphylline. In a two way crossover design twelve healthy male volunteers received a single 1000 mg dose of dyphylline orally as three conventional tablets (2 x 400 mg, 1 x 200 mg) or as a zero-order intravenous infusion (50 mg/min). A one week washout period separated administration of each dosage form. Plasma samples were collected over a 12 hour period and urine samples were collected for 48 hours post dosing. Urine and plasma samples were extracted and analyzed with high pressure liquid chromatography. Plasma drug concentration vs. time values after intravenous infusion were best described by a two compartment open model with first order elimination (average r² = 0.991 ± 0.007). The mean elimination half-life after intravenous administration calculated from the average β-value was 1.99 hours while the average half-life from the average β-value after oral administration was 1.87 hours. The mean absorption half-life calculated from the mean Ka was 12.2 minutes. Comparison of average AUC values obtained after administration of tablets (2829.7 meg x min/ml) to average AUC values after intravenous infusion (2944.6 meg x min/ml) indicates the mean biological availability was 96.5%. This is supported by urinary excretion data as an average of 768 mg of intact dyphylline was recovered in the urine after intravenous infusion and an average of 818 mg was recovered in the urine after oral administration of tablets. The urinary excretion ratio indicates the average oral bioavailability was 109%. It is concluded that dyphylline was rapidly and completely absorbed from the commercial tablet formulation investigated.
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