Clinical Pharmacokinetics of Theophylline

Abstract

Knowledge acquired of the kinetic disposition and effects of theophylline over the past 8 years has increased the clinical utility of the drug in the treatment of cardiorespiratory disorders. Although the anhydrous theophylline content varies greatly between products, there is similar excellent oral bioavailability. An average 96 % (range 75 to 105 %) of an uncoated theophylline tablet is absorbed, with peak concentrations occurring from 0.5 to 2.0h. Enteric coated and many sustained release preparations have poor bioavailability. Intravenous preparations of aminophylline contain from 75 to 85 % theophylline by weight. Other routes of administration are not to be recommended . . In plasma, some 53 to 65 % of theophylline is reversibly bound to protein. Premature neonates and adults with hepatic cirrhosis have reduced binding. The apparent volume of distribution in the steady state averages 0.5L/ kg body weight regardless of sex, age (J to 87 years), history of cigarette smoking, asthma, or acute pulmonary oedema. Premature neonates and adults with acidaemia, hepatic cirrhosis or obesity tend to have larger volumes of distribution for theophylline.Theophylline is eliminated by biotransformation in the liver and urinary excretion of its metabolites. Approximately 7 to 13 % is excreted unchanged in the urine by a first order process. One of the metabolites, 3 -methylxanthine, which is pharmacologically active but less potent than theophylline, is eliminated by Michaelis-Menten kinetics. Removal of dietary methylxanthines can increase the rate of elimination of a single dose of theophylline. Dose dependent elimination kinetics has been suggested but not conclusively demonstrated.The plasma theophylline concentration time curve after intravenous administration fits a 2 compartment open kinetic model with a rapid a distribution phase completed within 30 to 45 minutes after an intravenous dose. The ~ elimination phase (t 1I2~ is quite variable and in healthy adults ranges from 3 to 13h. As the apparent volume of distribution is little altered under most conditions, variations in theophylline elimination half-life reflect alterations in plasma theophylline clearance. The predominant factors which alter theophylline clearance are age, body weight, diet, smoking habits, other drugs and cardiorespiratory or hepatic disease.The elimination of theophylline is markedly decreased in premature infants and increased in childhood. The rapid clearance in childhood decreases toward adult values in the late teens. Some authors believe old age per se decreases an individual's capacity to eliminate theophylline. However, this may be a reflection of the inability of hepatic enzymes in the elderly to respond to factors in the diet or environment which usually stimulate theophylline clearance.The elimination half-life of theophylline is prolonged in obese subjects and maintenance doses must be calculated from ideal body weight. Theophylline clearance can be decreased by a high carbohydrate-low protein diet, as well as the ingestion of oth...

Combination of aminophylline (Phyllocontin Continus tablets) and salbutamol in the management of chronic obstructive airways disease.

“…The explanation for this difference is not clear. A recent review of the factors which affect theophylline clearance (Ogilvie, 1978) implicated increasing age, obesity, smoking and liver dysfunction as important elements which decrease the clearance of this drug and, therefore, which may increase the potential for developing toxicity. In the present study, however, these population characteristics do not appear biased in the direction of reduced theophylline clearance and cannot, therefore, account for the high prevalence of side effects which was observed.…”

Comparative pharmacokinetics of theophylline and aminophylline in man.

“…For few drugs have the dosage schedules been more meticulously designed after detailed pharmacokinetic studies in healthy volunteers and in patients from different age groups and with various pathological conditions (Ogilvie, 1978). By far the majority of these studies have been carried out with aminophylline, but some oral experiments with pure theophylline have also been published (Sansom, Milne & Cooper, 1979;Talseth, Boye & Bredesen, 1979).…”

The Treatment of Status Asthmaticus

“…GEORG tient (57). It was used in 276 patients (25) with bered that aminophylline contains 75-85% only two cases of pneumothorax, so the risk theophylline (95). does not seem to be high.…”

“…Theophylline has a mean half-life in Theophylline has for many years been among adults of about 4.5 h, with a range between 3 the first drugs administered to a patient admit-and 16 h (53,87,95,99). It is lower in chilted to hospital with an attack of severe asthma.…”

“…An improvement can be measured Theophylline is distributed in the organism within 15 min after a loading dose (78), whereas in a volume of about 0.5 1 per kg (41,95,105). it may take several hours before an improveThe estimated values range from about 0.30 to ment is noted during continuous infusion.…”