Abstract
Purpose
To evaluate the pharmacokinetic profile of tolvaptan.
Method
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.
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.
Similar content being viewed by others
References
Kondo K, Ogawa H, Yamashita H, et al. 7-Chloro-5hydroxy-1[2-methyl-4-(2-methylbenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061): a potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist. Bioorg Med Chem. 1997;7:1743–54.
Yamamura Y, Nakamura S, Itoh S, et al. OPC-41061, a highly potent human vasopressin V2-receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats. J Pharmacol Exp Ther. 1998;287:860–7.
Hirano T, Yamamura Y, Nakamura S, Onogawa T, Mori T. Effects of the V2-receptor antagonist OPC-41061 and the loop diuretic furosemide alone and in combination in rats. J Pharmacol Exp Ther. 2000;292:288–94.
Kato R, Yamazoe Y. Sex-specific cytochrome P450 as a cause of sex- and species-related differences in drug toxicity. Toxicol Lett. 1992;64/65:661–7.
Disclosures
None of the authors have any conflicts of interest associated with this study.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Furukawa, M., Umehara, K. & Kashiyama, E. Nonclinical Pharmacokinetics of a New Nonpeptide V2 Receptor Antagonist, Tolvaptan. Cardiovasc Drugs Ther 25 (Suppl 1), 83–89 (2011). https://doi.org/10.1007/s10557-011-6357-x
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10557-011-6357-x