Objective: Increased bioavailability of the P-glycoprotein (Pgp) substrates digoxin and cyclosporin due to erythromycin has been observed in vivo. The aim of the present study was to investigate the effect of orally administered erythromycin on the oral bioavailability of the β-blocker talinolol. Talinolol is a suitable model compound for Pgp drug-drug interaction studies due to its Pgp-related active intestinal secretion and lack of any significant metabolism. Methods: In a randomized crossover study, the oral pharmacokinetics of talinolol (50 mg) after a concomitant single oral dose of erythromycin (2 g) or placebo were investigated in 9 healthy men concentrations of talinolol were measured in serum and urine by HPLC. Results: The area under the curve of talinolol serum concentrations from 0 to 24 h (AUC((0-24))) and the maximum serum concentrations (C(max)) were significantly increased after administration of erythromycin compared to placebo, t(max) values were significantly reduced. The renal clearance (CL(R)) of talinolol was unchanged after co-administration of erythromycin and there was a small but statistically significant decrease in elimination half-life (t(1/2)). Serum pharmacokinetics correlate with the results derived from urine concentration measurement. One subject suffered from moderate diarrhea after erythromycin and was excluded from the analysis. Conclusion: We suggest that the increase in oral bioavailability of talinolol after concomitant erythromycin is caused by increased intestinal net absorption due to Pgp inhibition by erythromycin.