Simvastatin does not influence the intestinal P-glycoprotein and MPR2, and the disposition of talinolol after chronic medication in healthy subjects genotyped for the ABCB1, ABCC2 and SLCO1B1 polymorphisms.

AIMS: To evaluate whether simvastatin influences (i) the intestinal expression of P-glycoprotein (P-gp) and MRP2, and (ii) the disposition of the beta(1)-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 AUC(0-infinity) (r = 0.627, P = 0.039) and C(max) (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.

The talinolol double-peak phenomenon is likely caused by presystemic processing after uptake from gut lumen.

PURPOSE: Evaluation of the double-peak phenomenon during absorption of the beta(1)-selective blocker talinolol relative to paracetamol, which is well absorbed from all parts of the gut, and relative to vitamin A, which is absorbed via the lymphatic pathway. METHODS: Talinolol was given with paracetamol and retinyl palmitate in fast-disintegrating, enteric-coated, and rectal soft capsules to 8 fasting male healthy subjects (21-29 years, 68-86 kg). To evaluate whether the talinolol double-peak is associated with processes of food absorption, a breakfast was served 1 h after administration of a fast disintegrating capsule. RESULTS: Bioavailability of talinolol in enteric-coated and rectal capsules was significantly reduced by about 50% and 80%, respectively, despite unchanged bioavailability of paracetamol. Double-peaks appeared after 2-3 h and 4-6 h with talinolol given as fast-liberating capsules. Food increased the maximum concentrations significantly (223 +/- 76 microg/ml vs. 315 +/- 122 microg/ml, p < 0.05) and shifted the second peak of talinolol to shorter t(max) values (3.8 +/- 1.2 h vs. 2.1 +/- 0.6 h, p < 0.05), which was associated with faster absorption of retinyl palmitate. Pharmacokinetic model fits showed that about half of the oral talinolol dose given with and without meal is drained from the intestine via a presystemic storage compartment. CONCLUSIONS: 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.