Vitamin K prodrugs: 1. Synthesis of amino acid esters of menahydroquinone-4 and enzymatic reconversion to an active form

Pharm Res. 1995 Jan;12(1):18-23. doi: 10.1023/a:1016274201137.

Abstract

The efficacy and toxicity of vitamin K depends on the pathway and the extent of enzymatic reductive activation to vitamin K hydroquinone, which is an essential cofactor for the synthesis of clotting factors. Parenteral use of vitamin K is impaired by its water insolubility. With the aim to improve delivery problems associated with menahydroquinone-4 (MKH, 2), an active form of menaquinone-4, N,N-dimethylglycine esters of 2 (1-mono, 4-mono, and 1,4-bis) were synthesized and assessed as potential water-soluble prodrugs for parenteral use. The esters can deliver the hydroquinone to its active site without a quinone reductive activation step. The hydrochloride salts of the esters were found to be quite soluble in water. The hydrolysis of the esters in 20% rat liver homogenate 9000 x g supernatant, rat plasma and phosphate buffer, pH 7.4, at 37 degrees C was kinetically studied in the presence and absence of an esterase inhibitor. The hydrolysis was catalyzed by esterases located in the rat liver and rat plasma and quantitatively yielded 2. These results suggest that esterification of 2 with N,N-dimethylglycine is a promising way for obtaining water-soluble prodrug forms of 2. Based on the high susceptibility to liver esterase, the esters are potential prodrugs for achieving the site-specific delivery of 2.

MeSH terms

  • Animals
  • Biotransformation
  • Chemical Phenomena
  • Chemistry, Physical
  • Drug Design
  • Esterases / antagonists & inhibitors
  • Esters / chemical synthesis*
  • Esters / chemistry
  • Esters / pharmacokinetics*
  • Hydrolysis
  • Hydroquinones / chemical synthesis*
  • Hydroquinones / chemistry
  • Hydroquinones / pharmacokinetics*
  • Infusions, Parenteral
  • Kinetics
  • Lipids / chemistry
  • Prodrugs / chemical synthesis*
  • Prodrugs / chemistry
  • Prodrugs / pharmacokinetics*
  • Rats
  • Solubility
  • Vitamin K / analogs & derivatives*
  • Vitamin K / chemical synthesis
  • Vitamin K / chemistry
  • Vitamin K / metabolism
  • Vitamin K / pharmacokinetics*
  • Vitamin K 2* / analogs & derivatives*
  • Water / chemistry

Substances

  • Esters
  • Hydroquinones
  • Lipids
  • Prodrugs
  • Water
  • Vitamin K 2
  • Vitamin K
  • menahydroquinone-4
  • Esterases