Hypoxia, Arterial pH and Theophylline Disposition

Abstract

Theophylline is a bronchodilator used extensively in the management of obstructive pulmonary disease. Factors implicated in altered theophylline clearance include smoking, age, concomitant drug intake, liver disease and left ventricular heart failure. However, evidence now suggests that theophylline clearance may be altered by changes in severity of the pulmonary obstruction, hypoxia and variation in arterial pH. The in vitro disposition of theophylline has been evaluated in isolated rat livers and mouse hepatocytes. In vivo studies have assessed the metabolism of theophylline under hypoxia in rats, rabbits and dogs. In isolated mouse hepatocytes and rat livers, low oxygen concentrations resulted in higher theophylline concentrations, a longer elimination half-life and a decrease in the production of the metabolite 1,3-dimethyl uric acid, suggesting impaired metabolism of theophylline. In rabbits, hypoxia, hypercapnia and respiratory acidosis decreased total body clearance and increased plasma theophylline concentrations. On the other hand, experiments involving dogs showed no significant changes in theophylline concentrations or pharmacokinetic parameters with hypoxia. At present, animal studies remain inconclusive. This can be attributed to the use of different animal models and variations in study methodology, including the extent and duration of hypoxia and acidaemia, concurrent acid-base disorders such as hypercapnia, as well as the severity of pulmonary obstruction. Human studies assessing alterations in theophylline disposition secondary to the hypoxia present in pulmonary disease are few and include mostly case reports and observational studies. There is evidence suggesting decreased theophylline clearance and protein binding during acute illness and some consensus can be achieved using case reports and controlled studies. There is additional evidence that drug clearance decreases with age and that elderly patients may have a decreased theophylline clearance at baseline. However, the most obvious markers appear to be the severity of pulmonary disease and the rate of change in the patient's condition. Caution should be exercised when administering theophylline to elderly patients with chronic obstructive pulmonary disease presenting with acute exacerbations of a concomitant respiratory illness, as these patients appear to be most likely to exhibit altered theophylline metabolism. Therefore, they would be at increased risk for toxicity should conventional dosages be used during an acute respiratory event.

Simultaneous Quantification of Diazepam and Dexamethasone in Plasma by High-Performance Liquid Chromatography with Tandem Mass Spectrometry and Its Application to a Pharmacokinetic Comparison between Normoxic and Hypoxic Rats

“…Several studies have indicated that hypoxia alters the pharmacokinetic characteristics of some drugs. Patients with chronic obstructive lung disease (COLD), pulmonary edema, pulmonary heart disease or congestive heart failure show significantly reduced theophylline clearance [ 6 ]. Compared with the data without hypoxia, the half-life of antipyrine was increased by 120% in patients with chronic hypoxemia, while the half-life of tolbutamide was decreased by 33% in patients with chronic asthma exposed to hypoxic conditions and tolbutamide clearance was increased by 180% in hypoxic subjects compared with controls [ 3 ].…”

Hypoxia‐induced down‐regulation of CYP1A1/1A2 and up‐regulation of CYP3A6 involves serum mediators

“…The clearance of theophylline can be decreased in patients with chronic obstructive lung disease, pulmonary oedema, pulmonary heart disease or congestive heart failure (Powell et al ., 1978). Since patients with these disease states present episodes of acute hypoxia, the decrease in theophylline metabolic clearance has been ascribed to hypoxia (Richer & Lam, 1993). Early in vivo and in vitro studies supported that acute hypoxia reduces the activity of multiple biotransformation pathways (Jones, 1981).…”

Effect of hypoxia alone or combined with inflammation and 3‐methylcholanthrene on hepatic cytochrome P450 in conscious rabbits

“…In animal models, non‐infectious inflammatory reactions, such as those induced by the injection of turpentine, carrageenan or Freund's adjuvant, also diminish the rate of biotransformation of xenobiotics (Beck & Whitehouse, 1974; Parent et al ., 1992). Although it is accepted that hypoxia and an inflammatory reaction individually depress the activity of the cytochrome P450 (P450) (Richer & Lam, 1993), in patients with advanced COLD, the effect of hypoxia on the P450 remains controversial (Cusack et al ., 1986; du Souich et al ., 1989), perhaps because the combined effect of hypoxia and an inflammatory reaction, as seen in patients with advanced COLD, on the P450 may not be as predicted from each individual condition.…”