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 β1-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 μg/ml vs. 315 ± 122 μg/ml, p ‹ 0.05) and shifted the second peak of talinolol to shorter tmax 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.