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Related Experiment Videos

Nonlinear theophylline elimination

D D Tang-Liu, R L Williams, S Riegelman

    Clinical Pharmacology and Therapeutics
    |March 1, 1982
    PubMed
    Summary
    This summary is machine-generated.

    Theophylline elimination kinetics and its metabolites show capacity-limited formation within therapeutic ranges. Metabolite elimination is rate-limited by theophylline clearance, with renal clearance dependent on urine flow.

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    Area of Science:

    • Pharmacokinetics
    • Drug Metabolism
    • Clinical Pharmacology

    Background:

    • Theophylline is a widely used medication for respiratory diseases.
    • Understanding its elimination kinetics and metabolite profiles is crucial for safe and effective dosing.
    • Previous studies have suggested complex elimination pathways for theophylline and its metabolites.

    Purpose of the Study:

    • To investigate the elimination kinetics of theophylline and its major metabolites in healthy adults.
    • To characterize the metabolic pathways and determine the kinetic parameters (Vmax, Km) for metabolite formation.
    • To assess the influence of urine flow on theophylline's renal clearance.

    Main Methods:

    • Single-dose and multiple-plateau pharmacokinetic studies were conducted in 14 healthy adults.

    Related Experiment Videos

  • Plasma concentrations of theophylline and metabolites (3-methylxanthine, 1-methyluric acid, 1,3-dimethyluric acid) were monitored.
  • Michaelis-Menten kinetics were applied to model metabolite formation, and computer fitting was used to obtain kinetic parameters.
  • Theophylline urinary excretion and renal clearance were measured, with particular attention to urine flow rates.

    • Main Results:

    • Theophylline metabolite formation followed Michaelis-Menten kinetics and became capacity-limited within the therapeutic range.
    • Apparent Vmax values for 3-methylxanthine, 1-methyluric acid, and 1,3-dimethyluric acid formation were 5, 13, and 34 mg/hr, respectively.
    • Metabolite elimination was rate-limited by theophylline elimination, and renal clearance of theophylline was highly dependent on urine flow.
    • Convex-descending plasma concentration curves were observed only at lower theophylline concentrations, below 1 mg/l.

    Conclusions:

    • Theophylline metabolism exhibits capacity-limited kinetics, particularly within the therapeutic dosage range.
    • The elimination of major theophylline metabolites is intrinsically linked to theophylline's own elimination rate.
    • Factors like diuresis and distribution phases can influence the observed plasma theophylline decay, masking saturable metabolism at higher concentrations.