Solifenacin is a novel muscarinic receptor antagonist for the treatment of the overactive bladder syndrome. We have performed in vitro studies to determine its potential for drug-drug interactions at the level of plasma protein binding and the P-glycoprotein MDR1 transcellular transporter. Plasma protein samples were incubated with [¹⁴C]-solifenacin and/or indicated other drugs at 37°C. An aliquot of the mixture was transferred to an ultrafiltration tube and centrifuged. The radioactivity in the filtrate was then related to that in the plasma protein solution. Data are means ±  SD of three experiments unless otherwise stated.

To identify the plasma protein fractions binding solifenacin, 100 and 1000 ng ml^-1 [¹⁴C]-solifenacin were incubated with human serum albumin (40 mg ml^-1), ₁-acid glycoprotein (1 mg ml^-1), high density lipoprotein (3 mg ml^-1), low density lipoprotein (3 mg ml^-1) or γ-globulin (10 mg ml^-1). Binding was highest to ₁-acid glycoprotein (86.0–89.2%) with less binding to albumin (57.4–60.0%), high density lipoprotein (49.0–49.8%), and low density lipoprotein (46.1–49.1%) and least to γ-globulin (8.2–10.9%). The potential for drug-drug interactions of solifenacin at the plasma protein binding level was studied using unfractionated plasma from three healthy volunteers. Total plasma protein binding of 100 ng ml^-1 [¹⁴C]-solifenacin was 95.2 ± 0.4% to 95.4 ± 0.4%, and this was not significantly affected by warfarin (1 and 2.5 µg ml^-1), ibuprofen (10 and 50 µg ml^-1) or salicylic acid (5 and 100 µg ml^-1). In reverse experiments, 100 and 1000 ng ml^-1 solifenacin did not significantly affect the plasma protein binding of 1 µg ml^-1 [¹⁴C]-warfarin (98.6 ± 0.2%), 10 µg ml^-1 [³H]-ibuprofen (99.3 ± 0.1%) or 5 µg ml^-1 [¹⁴C]-salicylic acid (91.3 ± 0.4%).

Studies on transcellular transport were done in LLC-PK1 cells transfected with the human MDR1 or an empty vector. Upon incubation with 1 µm [¹⁴C]-solifenacin for 1–4 h, flux ratios (basal-to-apical vs apical-to-basal) were close to unity irrespective of expression of MDR1, indicating a lack of transport by MDR1. In contrast the flux ratio of [³H]-digoxin (0.1 µm) during a 4 h incubation was 5.1 (235 ± 42/46 ± 4 µl mg^-1 protein h^-1) in MDR1-expressing but only 1.5 in control cells. Solifenacin (0.3–10 µm) concentration-dependently reduced [³H-digoxin flux ratios in MDR1-expressing cells resulting in an estimated IC₅₀ of 5.1 µm. An almost complete inhibition of [³H]-digoxin transport was also seen with 10 µm verapamil.

We conclude that ₁-acid glycoprotein is the main source of plasma protein binding of solifenacin. Solifenacin does not interact with warfarin, ibuprofen or salicylic acid at the level of plasma protein binding. It is not a substrate for MDR1 but can inhibit transport of digoxin, albeit only at concentrations markedly in excess of its affinity at M₃ muscarinic receptors (10 nM, [1]). These studies do not point to a major potential for pharmacokinetic drug-drug-interactions of solifenacin.

1. Ikeda, K, et al. Naunyn-Schmiedeberg’s Arch Pharmacol 2002; 366: 97.