Masayuki Furukawa1, Ken Umehara, Eiji Kashiyama. 1. Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd, 463-10 Kagasuno, Kawauchi-cho, Tokushima, 771-0192, Japan. m_furukawa@research.otsuka.co.jp
Abstract
PURPOSE: To evaluate the pharmacokinetic profile of tolvaptan. METHOD: The nonclinical pharmacokinetic profile of [(14)C]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. RESULTS: 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.
PURPOSE: To evaluate the pharmacokinetic profile of tolvaptan. METHOD: The nonclinical pharmacokinetic profile of [(14)C]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. RESULTS: 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.
Authors: Yang Lu; Jason R Slizgi; Kenneth R Brouwer; Robert L St Claire; Kimberly M Freeman; Maxwell Pan; William J Brock; Kim L Brouwer Journal: Drug Metab Dispos Date: 2016-03-24 Impact factor: 3.922
Authors: Merrie Mosedale; J Scott Eaddy; O Joseph Trask; Natalie S Holman; Kristina K Wolf; Edward LeCluyse; Brenton R Ware; Salman R Khetani; Jingtao Lu; William J Brock; Sharin E Roth; Paul B Watkins Journal: Toxicol Sci Date: 2018-01-01 Impact factor: 4.849
Authors: Nastaran Daneshgar; Peir-In Liang; Renny S Lan; McKenna M Horstmann; Lindsay Pack; Gourav Bhardwaj; Christie M Penniman; Brian T O'Neill; Dao-Fu Dai Journal: Kidney Int Date: 2021-12-22 Impact factor: 18.998
Authors: Jeffrey L Woodhead; William J Brock; Sharin E Roth; Susan E Shoaf; Kim L R Brouwer; Rachel Church; Tom N Grammatopoulos; Linsey Stiles; Scott Q Siler; Brett A Howell; Merrie Mosedale; Paul B Watkins; Lisl K M Shoda Journal: Toxicol Sci Date: 2016-09-21 Impact factor: 4.849