The double-peak phenomenon of talinolol is likely caused by a presystemic storage compartment, which represents the complex interplay of heterogeneous uptake and kick-back transport processes along the intestinal-hepatic absorption pathway.

Aims To evaluate whether simvastatin influences (i) the intestinal expression of P‐glycoprotein (P‐gp) and MRP2, and (ii) the disposition of the β1‐selective blocker talinolol, a substrate of these transporter proteins. Methods The disposition of talinolol after intravenous (30 mg) and single or repeated oral administration (100 mg daily) was monitored before and after chronic treatment with simvastatin (40 mg daily) in 18 healthy subjects (10 males, eight females, body mass index 19.0–27.0 kg m−2) genotyped for ABCB1, ABCC2 and SLCO1B1 polymorphisms. The steady‐state pharmacokinetics of simvastatin was evaluated before and after repeated oral talinolol administration. The duodenal expression of ABCB1 and ABCC2 mRNA before and after simvastatin treatment was quantified using real‐time reverse transcriptase‐polymerase chain reaction (TaqMan®). Results Simvastatin did not influence the expression of duodenal ABCB1 and ABCC2. There was no significant pharmacokinetic interaction between simvastatin and talinolol. Duodenal ABCB1 mRNA content was significantly correlated with the AUC0–∞ (r = 0.627, P = 0.039) and Cmax (r = 0.718, P = 0.013) of oral talinolol. The ABCB1 and ABCC2 gene polymorphisms did not influence simvastatin and talinolol disposition. The half‐life of the latter was significantly shorter in the nine carriers with a SLCO1B1*1b allele compared with the seven subjects with the wild‐type SLCO1B1*1a/*1a genotype (12.2 ± 1.6 h vs. 14.5 ± 1.4 h, P = 0.01). Conclusions Simvastatin does not influence the intestinal expression of P‐gp and MRP2 in man. There was no pharmacokinetic interaction between talinolol and simvastatin during their chronic co‐administration to healthy subjects.