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THEOPHYLLINE PHARMACOKINETICS

Theophylline pharmacokinetic parameters
Oral bioavailability (F) 96%
Clearance CL) 3 L/h
Volume of distribution (Vd) 35 L
Half-life (t1/2) 8 h
Commun drugs that influence theophylline metabolism
Induce metabolism Inhibite metabolism
Significantly Significantly
Phenobarbital Cimetidine
Phenytoin Ciprofloxacin
Rifampicin Disulfuram
Hydrocarbons (smoke) Oral contraceptives
  Propanolol
  Erythromycin
  Fluvoxamine

Description

Theophylline is used in the treatment of reversible airway obstruction due to chronic asthma, chronic bronchitis, or COPD. Both the bronchodilator and the adverse effects are closely related to drug concentration.

Theophylline is well absorbed when taken orally as a rapid-release tablet or when administered as a liquid solution. Bioavailability and rate of absorption of controlled-release preparations are more variable and influenced by formulation and food intake.

Theophylline distributes rapidly into fat-free tissues and body water. 40% is bound to plasma proteins, primarily to albumin, although blood pH values, the plasma protein content and the administration of concomitant drugs may vary this fraction. Theophylline passes freely across the placenta, into breast milk and into cerebrospinal fluid.

Theophylline is primarily eliminated by hepatic metabolism involving isoenzymes of the cytochrome P450 system. This metabolism has been assumed to follow first order kinetics (in some patients, nonlinear kinetics may be observed at therapeutic concentrations). Age and disease are the major endogenous factors influencing metabolism: clearance is markedly reduced in the neonates and elderly and increased in the first decade of life. Cirrhosis reduces clearance of theophylline, as does congestive heart failure. Exogenous factors such as concomitantly administered drugs, smoking and nutritional factors affect biotransformation by inducing or inhibiting the metabolizing enzymes: low-carbohydrate and high protein diet, active and passive smoking are associated with a significant increase in theophylline clearance.

Renal elimination of unchanged drug accounts for 10 to 15% of the total elimination of the dose in adults and may increase to up to 50% in neonates. Therefore, in a normal adult, renal disease has no significant effect on theophylline clearance.

Clinical implications

Estimation of the individual theophylline clearance should take into account the patients concomitant diseases, age and drug therapy. In patients with cor pulmonale, cardiac failure or end stage liver dysfunction, theophylline should be avoided if possible.

Because of intra- and inter-individual variability in the pharmacokinetics of theophylline, which may be increased by the presence of endogenous and/or exogenous factors, it is suitable to supervise theophylline therapy by therapeutic drug monitoring (TDM) for the target concentrations to be achieved.