Theophylline systemic clearance is decreased in a variety of disease states, eg, severe airway obstruction, COLD in the elderly, pneumonia, cor pulmonale, congestive heart failure, acute pulmonary edema, and hepatic failure. Theophylline hepatic extraction ratio, expressed as the ratio of the rate of extraction (arterial less venous concentrations) to the rate of presentation (arterial concentration), is low and its plasma protein binding is only 50 percent. Thus, one may speculate that a decrease in theophylline clearance should be related to a reduction in its rate of biotransformation. In all the above diseases states except hepatic failure, the mechanism explaining this decrease remains obscure.
It has already been proposed that hypoxia might cause a reduction in theophylline rate of biotransformation. This hypothesis was supported by several reports showing that hypoxia decreased the in vivo biotransformation of several substrates. More recent studies, using hepato-cytes, isolated perfused liver or conscious rabbits, have also shown that the clearance of theophylline was decreased under hypoxic conditions. http://mycanadianfamilypharmacy.net/
Studies conducted in man, however, have been contradictory and have not established definitely whether hypoxia causes a decrease in the activity of the cytochrome P-450. One study, comprised of patients with COLD, showed that arterial Pa02 values below 55 mm Hg increased antipyrine half life; however, these results were not confirmed by a more recent report. Other studies have shown that in patients with COLD, tolbutamide half life was reduced. On the other hand, in a pediatric population, as well as in critically ill patients, no correlation was found between arterial blood gases and theophylline clearance. Moreover, no decrease in theophylline clearance was observed in ten patients, with advanced COLD, when their chronic 02 therapy was discontinued.