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In vitro and in vivo pharmacological profile of OPC-61815, a water-soluble phosphate ester pro-drug of tolvaptan.
Fujiki, Hiroyuki; Matsunaga, Masayuki; Furukawa, Masayuki; Yamashita, Tatsuya; Nakamura, Shigeki; Miyazaki, Toshiki; Mizuguchi, Hiroshi; Menjo, Yasuhiro; Matsuda, Takakuni; Yamada, Yoshihisa.
Afiliación
  • Fujiki H; Department of Renal and Cardiovascular Research, Otsuka Pharmaceutical Co.Ltd., Tokushima, Japan. Electronic address: Fujiki.Hiroyuki@otsuka.jp.
  • Matsunaga M; Tokushima Research Institute, Otsuka Pharmaceutical Co.Ltd., Tokushima, Japan.
  • Furukawa M; Tokushima Research Institute, Otsuka Pharmaceutical Co.Ltd., Tokushima, Japan.
  • Yamashita T; Department of Research Management, Otsuka Pharmaceutical Co.Ltd., Tokushima, Japan.
  • Nakamura S; Department of Research Management, Otsuka Pharmaceutical Co.Ltd., Tokushima, Japan.
  • Miyazaki T; Tokushima Research Institute, Otsuka Pharmaceutical Co.Ltd., Tokushima, Japan.
  • Mizuguchi H; Department of Renal and Cardiovascular Research, Otsuka Pharmaceutical Co.Ltd., Tokushima, Japan.
  • Menjo Y; Department of Medicinal Chemistry, Otsuka Pharmaceutical Co.Ltd., Tokushima, Japan.
  • Matsuda T; CMC Headquarters, Otsuka Pharmaceutical Co.Ltd., Tokushima, Japan.
  • Yamada Y; Department of Renal and Cardiovascular Research, Otsuka Pharmaceutical Co.Ltd., Tokushima, Japan.
J Pharmacol Sci ; 150(3): 163-172, 2022 Nov.
Article en En | MEDLINE | ID: mdl-36184121
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Profármacos / Antagonistas de los Receptores de Hormonas Antidiuréticas Límite: Animals / Humans Idioma: En Revista: J Pharmacol Sci Asunto de la revista: FARMACOLOGIA Año: 2022 Tipo del documento: Article Pais de publicación: Japón
Texto completo
Añadir a Mi BVS
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Profármacos / Antagonistas de los Receptores de Hormonas Antidiuréticas Límite: Animals / Humans Idioma: En Revista: J Pharmacol Sci Asunto de la revista: FARMACOLOGIA Año: 2022 Tipo del documento: Article Pais de publicación: Japón