Adrenergic down-regulation can occur rapidly in many tissues. Therefore beta 2-agonists might have a rapidly decreasing effect in time, which is a potential problem for the treatment of bronchial asthma. This in vivo study tested the hypothesis that theophyline can prevent adrenergic down-regulation. A randomised, double blind, placebo-controlled cross-over study was performed in eight healthy subjects. Terbutaline concentration-effect relationships were studied before and after one week of dosing of terbutaline, with or without theophylline. Slow-release terbutaline 5 mg daily was administered for 7 days in combination with either placebo or slow-release theophylline. Concentration-effect relationships of terbutaline after a single subcutaneous injection were studied before and after the 7 day terbutaline treatment. Eosinopenia and hypokalemia were the systemic effect parameters. Terbutaline concentration-time courses were described with a two-compartment model and those of theophylline with a polynomial equation. A hypothetical effect compartment model was applied to link terbutaline plasma concentration via an Emax model to the studied effects. The interaction of theophylline and terbutaline was described with a non-competitive pharmacodynamic model. After one week of oral terbutaline, the mean EC50 (ng/L) of terbutaline increased for the eosinopenia from 1.87 +/- 1.66 to 3.78 +/- 2.18 (+102%) (p = 0.012) with placebo, and to 2.73 +/- 1.99 (+46%) (p = 0.025) with theophylline; for the hypokalemia the EC50 increased from 4.70 +/- 2.91 to 8.52 +/- 7.26 (+81%) (p = 0.012) with placebo, and to 5.64 + 2.59 (+20%) (p = 0.16) with theophylline. The results indicate that the non-specific phosphodiesterase inhibitor theophylline can prevent terbutaline-induced adrenergic down-regulation to a substantial degree.