Nonclinical Pharmacokinetics of a New Nonpeptide V2 Receptor Antagonist, Tolvaptan

To evaluate the pharmacokinetic profile of tolvaptan.

The nonclinical pharmacokinetic profile of [¹⁴C]tolvaptan was evaluated in an absorption, distribution, and excretion study in rats after single oral administration. An in vitro protein binding study was also performed.

The tolvaptan-derived radioactivity was rapidly absorbed and extensively distributed to all tissues in rats. The radioactivity levels were greatest in the gastrointestinal tract and liver, though the levels in the cerebrum, cerebellum and medulla oblongata were low. The serum and tissue concentrations of radioactivity, and serum concentration of tolvaptan in male and female rats showed a marked sex difference. The radioactivity was crossed the placenta and was distributed to the fetal tissues in pregnant rats. The milk showed 1.5–15.8-fold higher radioactivity than blood in lactating rats. The radioactivity mainly excreted into the feces via the biliary route. Tolvaptan binds extensively to plasma proteins (≥97.2%) in mouse, rat, rabbit, dog and human plasma.