The protective effect of choline theophyllinate, 600 mg orally, was studied by examining the effects on inhaled histamine, acetylcholine, and propranolol in 19 asthmatic patients. Only 9 of them showed a propranolol threshold. This bronchodilator significantly increased the threshold values of histamine and acetylcholine, but showed no protective effect on propranolol thresholds. The histamine threshold changed from 22.5 ± (SD)^1.2 to 2^{3.8 ± 1.0} mg/ml (p < 0.001). With acetylcholine an initial value of 24.2 ± 1.4 mg/ml was determined, which changed to 2^{5.5 ± 1.1} mg/ml (p < 0.01). The propranolol threshold changed from 1.17% ± 0.40 to 1.36% ± 0.40 indicating that theophylline has no statistically significant protective effect on propranolol inhalation. The re-producibility of the challenges was assessed in 8 control patients. A placebo did not significantly change the initial airway reactivity to the three agents. The protective effect of choline theophyllinate on histamine and acetylcholine correlated with the initial degree of reactivity on both agents (r = -0.60; p < 0.01 and r = -0.84; p < 0.001, respectively), whereas no significant correlation with the degree of bronchodilation was observed. The latter observation indicates that the protective effect of theophylline does not depend on its bronchodilating activity.

The systemic disposition of theophylline after taking a new, sustained release tablet (Theolair Retard 250 mg, Theolair S.R., Riker Laboratories) has been studied in 8 hospitalized patients. Absolute bioavailability was determined from the ratios of the areas under the serum concentration-time curves after intake of the tablet and after intravenous infusion of aminophylline in the same patient. The absolute bioavailability of Theolair Retard 250 mg was 110.9 +/- 20.8% (mean +/-SD). Maximal serum concentrations were reached after 7.3 +/- 3.5 h, the large intersubject variation being due to differences in gastric emptying time. The tablets appear to release theophylline slowly in acid conditions, but more rapidly in an alkaline medium. Invasion was found to be either monophasic with a rate constant of about 0.8 h-1 (intestine), or biphasic with rate constants of 0.2 h-1 (stomach) and 0.8 h-1 (intestine). The peak levels accounted for 7.9 +/- 2.2 mg . 1-1. The profiles of the serum concentration-time curves were such that the concentrations remained above 80% of cmax for 6.5 +/- 3.3 h. The relevant pharmacokinetic parameters (half-life of elimination, total body clearance and volume of distribution) were determined and were used to calculate the individual dosage regimens required to obtain therapeutic serum concentrations. The optimal dosing interval to obtain an average steady state serum concentration of 12.5 mg . l-1 was 9.8 +/- 3.1 h.

The correlation between serum and saliva levels of theophylline was investigated in seven healthy volunteers after multiple dose administration of a low dose (300 mg/day) and a high dose (900 mg/day) of a sustained release theophylline preparation (Theo-Dur). Tablets were taken for five days, at 8 a. m. and 8 p. m. and a last dose was taken on Day 6 at 8 a. m. Fourteen serum and saliva samples were collected simultaneously during the dosing period and for up to 32 h after the last dose. On the 300 mg/day regimen the level in saliva was 55.3% of the serum level, with an overall variability of 6.7% and an intrasubject variability of 10.5%. After 900 mg/day, the saliva concentration was 55.5% of the serum concentration, with an overall variability of 7.6% and an intrasubject variability of 12.7%. A good correlation was found between both determinations (r = 0.99), which suggests that saliva levels could be used to monitor theophylline after administration of a sustained release tablet.

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We have studied the pharmacokinetics of theophylline and enprofylline in patients with liver cirrhosis, patients with chronic renal failure, and healthy subjects, and have assessed the predictive value of routine tests of liver function and renal function (creatinine clearance) for theophylline and enprofylline total body clearances. Theophylline clearance was significantly decreased in the patients with liver cirrhosis compared with both the patients with renal failure and the healthy subjects (the mean values in the three groups were 24, 47, and 46 ml.h-1.kg-1 respectively. Enprofylline clearance was significantly decreased in the patients with chronic renal failure, compared with both the patients with liver cirrhosis and the healthy subjects (the values in the three groups were 64, 250, and 289 ml.h-1.kg-1 respectively. There was a strong correlation between creatinine clearance and enprofylline clearance, while there was only a poor correlation between the liver function tests and theophylline clearance. It appears that in various clinical situations enprofylline elimination can be predicted more precisely than theophylline elimination, which may make the drug safer in clinical practice.