Purpose: To quantitate the effect of verapamil administered orally, a calcium channel blocker and potent inhibitor of P-glycoprotein on oral pharmacokinetics of the β-adrenergic receptor antagonist talinolol, a substrate of P-glycoprotein. Subjects and Methods: In a randomized, crossover placebo-controlled study, oral pharmacokinetics of talinolol (50 mg) after concomitant administration of single doses of R-verapamil (120 mg) or placebo were investigated in 9 healthy volunteers. Concentrations of talinolol, verapamil, and its main metabolite norverapamil were measured in serum with HPLC. Concentrations of talinolol were also measured in urine by HPLC. Standard pharmacokinetic parameters were calculated with noncompartmental procedures. Results: The area under the concentration-time curve for talinolol from 0 to 24 hours was significantly decreased after R-verapamil versus placebo (721 ± 231 ng · h · mL^-1 versus 945 ± 188 ng · h · mL^-1; P < .0). Maximum serum concentration of talinolol was reached significantly earlier after R-verapamil compared with placebo (P < .05). Coadministration of R-verapamil did not affect the renal clearance or half- life of talinolol. Serum pharmacokinetics are paralleled by the results derived from urine concentrations of talinolol. Conclusion: This is the first study to show a decreased oral bioavailability of a P-glycoprotein substrate (talinolol) in humans as a result of coadministration of verapamil. This effect is assumed to be caused by changes of the intestinal net absorption of talinolol because its renal clearance remains unaffected by administration of R-verapamil. This unexpected effect of R-verapamil is most likely dose dependent as a result of an interplay between intestinal P-glycoprotein and gut metabolism.