2. Academic Validation
  3. In vitro and in vivo pharmacological profile of OPC-61815, a water-soluble phosphate ester pro-drug of tolvaptan

In vitro and in vivo pharmacological profile of OPC-61815, a water-soluble phosphate ester pro-drug of tolvaptan

  • J Pharmacol Sci. 2022 Nov;150(3):163-172. doi: 10.1016/j.jphs.2022.08.004.
Hiroyuki Fujiki 1,  Masayuki Matsunaga 2,  Masayuki Furukawa 2,  Tatsuya Yamashita 3,  Shigeki Nakamura 3,  Toshiki Miyazaki 2,  Hiroshi Mizuguchi 4,  Yasuhiro Menjo 5,  Takakuni Matsuda 6,  Yoshihisa Yamada 4
Affiliations

Affiliations

  • 1 Department of Renal and Cardiovascular Research, Otsuka Pharmaceutical Co.Ltd., Tokushima, Japan. Electronic address: [email protected].
  • 2 Tokushima Research Institute, Otsuka Pharmaceutical Co.Ltd., Tokushima, Japan.
  • 3 Department of Research Management, Otsuka Pharmaceutical Co.Ltd., Tokushima, Japan.
  • 4 Department of Renal and Cardiovascular Research, Otsuka Pharmaceutical Co.Ltd., Tokushima, Japan.
  • 5 Department of Medicinal Chemistry, Otsuka Pharmaceutical Co.Ltd., Tokushima, Japan.
  • 6 CMC Headquarters, Otsuka Pharmaceutical Co.Ltd., Tokushima, Japan.
PMID: 36184121 DOI: 10.1016/j.jphs.2022.08.004
Abstract

Tolvaptan is an orally active vasopressin V2 receptor antagonist and used for the treatment of volume overload in some disease as an aquaretic. Tolvaptan sodium phosphate (OPC-61815) is a pro-drug of tolvaptan that was designed to improve water solubility and enable intravenous use. The conversion of OPC-61815 to tolvaptan was evaluated for in vitro and in vivo pharmacokinetic studies. The pharmacodynamics of OPC-61815 were evaluated for in vitro receptor binding affinity, in vivo aquaretic and anti-edematous action. The solubility of OPC-61815 in water at 25 °C was 72.4 mg/mL and more than 100,000 times the solubility of tolvaptan. OPC-61815 was hydrolyzed to tolvaptan by human tissue S9 fractions and main Enzyme of hydrolysis was Alkaline Phosphatase. After intravenous administration of OPC-61815 to rats and dogs, tolvaptan was detected in plasma within 5 min and the bioavailability of tolvaptan was 57.7% and 50.9%, respectively. Binding affinity of OPC-61815 for the human V2 receptor was 1/14 weaker than that of tolvaptan. OPC-61815 exerted dose-dependent aquaretic action in rats and dogs and a corresponding anti-edematous action in rat edema models. These results suggest that OPC-61815, a water-soluble phosphate ester pro-drug of tolvaptan, is an effective aquaretic by converting to tolvaptan after intravenous administration.

Keywords

Pro-drug; V(2) receptor antagonist; Vasopressin.

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