Twelve volunteers participated in a two-way crossover trial in which the effects of ceftibuten on the pharmacokinetics of theophylline were evaluated. Subjects were given single intravenous doses of theophylline (4 mg/kg) with no ceftibuten treatment and on the sixth day of ceftibuten treatment. Ceftibuten 200 mg was taken orally twice daily (7:00 AM and 7:00 PM). A total of 13 blood samples per subject were collected over 48 hours following theophylline administration. Ceftibuten failed to alter either the systemic clearance of theophylline (CL), its volume of distribution (Vss), or its elimination half-life (t1/2). The 24-hour plasma theophylline concentration measured both by high performance liquid chromatography (HPLC) or fluorescence polarization immunoassay (FPIA) was used for a single sample estimate of theophylline clearance (CL), and it was found to provide a suitable estimate of the multisample value for CL.