INFLUENCE OF ENDOGENOUS AND EXOGENOUS EFFECTORS ON THE PHARMACOKINETICS OF THEOPHYLLINE - FOCUS ON BIOTRANSFORMATION

Theophylline has been widely used as a bronchodilatory drug for the tr eatment of neonatal apnoea in premature newborns and patients with obs tructive airways disease. The development of analytical equipment and procedures to determine the systemic concentration of theophylline ren ders it possible to improve the effectiveness of theophylline therapy and reduce the incidence of toxic and adverse effects. Since the begin ning of the 1970s, endogenous and exogenous factors (e.g. age, blood p H, concomitant diseases and drug therapy, meal preparation procedures, nutritional habits, pregnancy, gender, smoking and, to a lesser exten t, biorhythms), influencing nearly all parameters of theophylline phar macokinetics have been described. Drug absorption depends on galenic f ormulation, drug delivery, nutritional habits and the chemical derivat ives used, The mean plasma protein binding rates depend on the method of plasma protein determination: acidic blood pH values and advanced a ge may result in reduced plasma proteins. The volume of distribution d epends primarily on age; it is 2-fold greater in newborns than in adul ts. Furthermore, changes in blood pH values, the plasma protein conten t and the administration of concomitant drugs may vary this parameter, Biotransformation is the most clinically important pharmacokinetic pa rameter. Hepatic metabolism accounts for 90% of the metabolism of theo phylline. Essentially, 2 microsomal isoenzymes of the cytochrome P450 system appear to be responsible for the N-methylation and 8-hydroxylat ion of the drug. Age and concomitant disease are the major endogenous effecters influencing biotransformation of theophylline, whereas biorh ythms, gender and pregnancy are of lesser importance. Exogenous factor s, such as concomitantly administered drugs, smoking and nutritional f actors, affect biotransformation by inducing or inhibiting the metabol ising enzymes. Because of intra- and interindividual Variability in th e pharmacokinetics of theophylline, which may be increased by the pres ence of endogenous and/or exogenous effecters, it is necessary to supe rvise theophylline therapy by therapeutic drug monitoring if target co ncentrations are to be achieved.