1. The serum protein binding of theophylline was studied in 28 asthmatics and 11 patients with cystic fibrosis (CF) who were receiving the drug regularly. Peak theophylline samples were collected at 2 week intervals on four occasions in each asthmatic and on three occasions in each CF patient. The binding was measured using ultrafiltration at 37 degrees C and pH 7.4. The total and free (unbound) theophylline concentrations were measured using high‐performance liquid chromatography. 2. The mean free‐fractions (+/‐ s.d.) in asthmatics (0.50 +/‐ 0.03) and in CF patients (0.51 +/‐ 0.04) were not significantly different. The intra‐ and inter‐subject variability in the free‐fraction (fu) was relatively small in both patient groups. The binding was found to be concentration‐independent at serum theophylline concentrations up to 30.9 micrograms ml‐1. The effects of age, gender, serum albumin and total serum protein on the free fraction were evaluated. 3. The results indicate that the binding of theophylline is similar in the two disease states. The low degree of variability in serum theophylline binding indicates that measurements of total serum theophylline concentrations will reflect unbound serum concentrations with acceptable accuracy in both patient groups studied.

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Theophylline levels in mixed saliva (both stimulated and unstimulated) were compared with total and free (unbound) serum theophylline levels in 28 asthmatic outpatients using theophylline regularly. Stimulated saliva predicted both total and unbound serum theophylline concentrations within +/- 1 microgram/mL in 62.5% and 92.9%, respectively, of the samples examined. In addition, the total serum levels could be used to predict unbound serum concentrations to within +/- 1 mg/L in 100% of the cases that were examined. These results indicate that saliva levels predict the unbound serum theophylline levels with greater accuracy and precision than they predict total serum theophylline levels. In addition, total serum levels can be used to reliably predict unbound serum levels. The use of mixed stimulated saliva is recommended as a reliable non-invasive method for monitoring unbound serum theophylline levels. The therapeutic range for saliva, which corresponds to the accepted total serum concentration range of 10-20 mg/L, is approximately 5.6-11.3 mg/L.

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A rapid, specific high-performance liquid chromatographic analysis of theophylline in plasma, serum, and saliva is described. Proteins present in the biological samples are precipitated with 6% perchloric acid and the clear supernatant is chromatographed on a reversed-phase column. Only 100 microL of serum is required and concentrations as low as 0.07 micrograms/mL can be measured accurately. Other xanthines do not interfere in the assay. Within- and between-day variation is less than or equal to 2.2%. The method shows less bias and greater precision than the TDx (Abbott Diagnostics) procedure commonly used in clinical laboratories.