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The disposition of intravenous doses of theophylline was determined in normal male subjects before and after treatment with phenobarbital 2 wk. Although there was some variation in disposition of the 2 drugs, there were no significant effects of phenobarbital on theophylline kinetics. We conclude that theophylline dosage need not be altered during concomitant administration of phenobarbital.

To characterize further the pharmacokinetics of theophylline in premature infants, its concentraion in blood was measured by high-pressure liquid chromatography after intravenous infusion given to six apneic premature newborns three to 15 days of age. Theophylline's apparent volume of distribution was 0.690 +/- 0.095 liters per kilogram (mean +/- S.E.), a value similar to that of children, but the half-life (30.2 +/- 6.5 hours) was nine times longer. Blood clearance rate (17.6 +/- 2.3 ml per kilogram per hour) was lower than plasma clearance rate (100 ml per kilogram per hour) of young children. At a total plasma concentration of 17 mg per liter, 56.4 +/- 3.8 and 36.4 +/- 3.8 per cent of the theophylline was bound to adult or full-term cord plasma proteins, respectively. Bilirubin and theophylline did not compete for plasma protein. Calculations suggest that a loading doses of 5.5 mg per kilogram and a maintenance dose rate of 1.1 mg per kilogram per eight hours would achieve and maintain a mean blood concentration of 8 mg per liter (about 10 mg per liter in plasma).

We studied the pulmonary disposition of theophylline by performing bronchoalveolar lavage on 19 normal, nonsmoking volunteers who had taken theophylline orally for 14 days. In addition, we determined the influence of theophylline on human alveolar macrophage bacterial phagocytosis, intracellular killing, and hydrogen peroxide release. We found a 1:1 relationship between serum and bronchoalveolar lavage theophylline concentrations when lavage fluid concentrations were corrected for saline dilution. We found marked impairment of the bactericidal activity of alveolar macrophages from theophylline-treated subjects (intracellular killing efficiency of 24.7 +/- 1.5% compared with 60.2 +/- 0.9% by macrophages from control subjects; p less than 0.001). This defect in alveolar macrophage bactericidal activity was inversely correlated with the bronchoalveolar lavage theophylline concentrations, and was corrected after the alveolar macrophages were cultured under serum-free conditions for 48 h. Theophylline significantly impaired alveolar macrophage release of hydrogen peroxide. Hence, theophylline may compromise lung host defenses by suppressing alveolar macrophage bactericidal activity and oxidative metabolite release.

We studied the steady-state disposition of slow release theophylline tablets and granules in 12 institutionalized (I) and 12 community-dwelling (C) elderly patients with fixed chronic obstructive lung disease. Design was open label with random order crossover; each formulation was given 5 min before food every 12 h for 7 days. Age (median 70 y, range 55-88), sex, smoking status, and baseline lung function off drug were similar. Though plasma concentration (Cp) was higher with the tablets as was the area under the Cp vs time curve: 134 (74-252) vs 121 (75-197) mg h l-1; p = 0.028. The standard deviation of Cp over one dose interval was lower with the granules. FEV 1.0 was slightly improved over baseline. Dose required to reach target Cp was higher in the institutionalized group (12.6 vs 8.6 mg kg-1 day-1; p = 0.003) as was apparent clearance; I:94 (43-148) ml hr-1 kg-1 vs C:68 (34-163); p = 0.003. Although bioavailability was slightly reduced for the granules, fluctuations of Cp was less, and we failed to find a food effect that was clinically important in geriatric subjects.

We present a specific, sensitive high-pressure liquid-chromatographic assay for theophylline in plasma. Only 0.5 ml of plasma is required for each determination, and the lower limit of detection by this method is 0.1 mg/liter. Other xanthines and their metabolites do not interfere. This method is suitable for use in studying the pharmacokinetics of this drug in infants and children, from whom only small volumes of blood are available.

The disposition of a single intravenous dose of theophylline, 3.2 mg/kg, was studied using a high-pressure liquid chromatographic assay in ten asthmatic children one to four years of age. The man plasma theophylline clearance was 0.100 +/- 0.036 l/kg/hr, kel 0.49 +/- 0.30 hr-1, betat1/2 3.38 +/- 1.11 hr, alphat1/2 0.13 +/- 0.09 hr, and V1 0.25 +/- 0.13 1/kg. Plasma theophylline clearance was approximately 40% greater in these children than that reported in adults, mainly due to an increased rate of drug elimination. Large interindividual differences were observed. Analysis of data using either a two- or one-compartment model yielded almost identical dosage regimens designed to rapidly achieve and maintain a chosen plasma theophylline concentration. Calculations based upon mean values of pharmacokinetic constants predict that a maintenance dose rate for aminophylline of 30 mg/kg/day, after a loading dose of 5.6 mg/kg, would rapidly achieve and maintain a mean steady-state plasma concentration of theophylline of 10 mg/1. Potential toxicity of such a regimen has not been excluded, since therapeutic trials (with achievement of steady state) have not yet been conducted.

To determine the role of liver dysfunction in theophylline toxicity, we administered single intravenous doses of the drug to nine patients with cirrhosis and observed its disposition over a period of 24 to 48 hours. As compared to 19 normal subjects, these patients had a prolonged plasma half-life (mean, 25.6 vs. 6.7 hours) and a decreased plasma clearance (mean, 0.042 vs. 0.062 liter[kg-1]hr-1). Volumes of distribution of theophylline in the cirrhotic patients (central-compartment volume of 0.330, and steady-state volume of distribution of 0.785 liter per kilogram) did not substantially differ from normal (0.246 and 0.508 respectively). Plasma theophylline binding in three patients with cirrhosis averaged 36.8 per cent as compared to 52.6 per cent in four normal subjects. There was no correlation between any laboratory test of liver function and the plasma theophylline half-life, except for serum albumin (r = 0.92, P less than 0.001). The variable capacity to eliminate theophylline precludes the use of usual maintenance dose schedules for bronchodilation in cirrhosis.

Nine patients with acute cardiogenic pulmonary edema were given theophylline intravenously, and its disposition was observed over the next 24 hr. Compared to that in 19 normal subjects, these patients had prolonged plasma half-lifes (mean, 22.9 from 6.7 hr) and decreased plasma clearances of theophylline (mean, 0.041 from 0.062 L [kg-1] hr-1). The intersubject variation in these parameters was 20-fold in patients with pulmonary edema and 4-fold in normal subjects. Since the peak plasma concentrations attained and the apparent volumes of distribution were not different in the two groups, a suitable initial dose can be calculated. A loading dose of 4.5 to 5 mg/kg theophylline (6 mg/kg aminophylline) given over 20 min appears safe. Because of the great variability in the plasma clearance of this drug in patients with heart failure, plasma concentrations and toxicity would be unpredictable after repeated doses or constant infusions.