Solifenacin is a novel muscarinic receptor antagonist for the treatment of the overactive bladder syndrome. We have investigated the disposition of [¹⁴C]-labelled solifenacin in healthy volunteers, characterized its in vitro metabolism by human liver microsomes and CYP isoenzymes, and determined whether solifenacin or its major metabolites inhibit CYP isoenzymes.

[¹⁴C]-labelled solifenacin succinate (10 mg, 1.5 MBq in 50 ml water) was given orally to four healthy male subjects. The pharmacokinetic profiles of the total radioactivity and of solifenacin were followed for 12 days with monitoring of excretion in urine, faeces and exhaled air. The in vitro metabolism of solifenacin (0.1–200 µm) was determined upon co-incubation (1 h at 37°C) with human liver microsomes and with CYP isoenzymes expressed in insect cell Supersomes. Concentrations of solifenacin and its major metabolites were quantified by LC-MS. Data are means ± SD unless otherwise mentioned.

The radioactivity in plasma was consistently higher than in whole blood (C_max 19.8 ± 2.9 vs 13.1 ± 2.2 ng ml^-1, p = 0.0021 in a paired t-test; AUC(0, ) 1794 ± 460 vs 770 ± 185 ng ml^-1 h, p = 0.0077), whereas t_max was similar (5.3 ± 1.0 vs 5.3 ± 1.5 h). 69.2 ± 7.8%, 22.5 ± 3.3% and 0.4 ± 0.8% of the administered radioactive dose were recovered in urine, faeces and exhaled air, respectively. The radioactivity in plasma was largely accounted for by solifenacin, whereas that in urine was largely due to its metabolites. The half-life of elimination for unchanged solifenacin ranged from 38–86 h. To elucidate differences in plasma and whole blood concentrations, in vitro experiments were performed in which whole human blood was incubated with 10, 50 or 250 ng ml^-1 [¹⁴C]-solifenacin at 37 ° C for 10 min (n = 3). This yielded cell-to-plasma concentration ratios of 0.74 ± 0.21, 0.63 ± 0.24 and 0.80 ± 0.04, respectively.

The in vitro metabolism of solifenacin by human liver microsomes was measured. Formation of metabolites M2 (solifenacin-N-oxide) and M3 (4R-hydroxysolifenacin) occurred with a K_m of 64-93 and 43–56 µm, respectively, and a V_max of 393–440 and 55–62 pmol min^-1 mg^-1 protein, respectively (n = 2). In in vitro studies with 14 cDNA expressed CYP isoenzymes, formation of M3 was largely by CYP3A4 with very minor contributions by CYP1A1 and CYP2D6. M2 was formed by many isoenzymes. The secondary metabolite M4 (4R-hyodroxysolifenacin-N-oxide) was formed by CYP3A4. Solifenacin inhibited human CYP1A2, 2C9, 2C19, 2D6 and 3A4 with IC₅₀ values of > 250, 214 ± 33, 31 ± 1, 74 ± 1 and 110 ± 13 µm, respectively (n = 4 each). Metabolites M3 and M4 and solifenacin-N-glucuronide (M5) were even less potent inhibitors.

We conclude that solifenacin is metabolized extensively. It is primarily excreted in urine in metabolized form, and CYP3A4 appears the major enzyme responsible for its metabolism. However, clinically relevant concentrations of solifenacin or its metabolites are unlikely to inhibit CYP3A4 or other CYP isoenzymes.