Vitamin K Prodrugs: 2. Water-Soluble Prodrugs of Menahydroquinone-4 for Systemic Site-Specific Delivery

Jiro Takata, Yoshiharu Karube, Mitsunobu Hanada, Kazuhisa Matsunaga, Yoshikazu Matsushima, Toshiaki Sendo, Ryozo Oishi

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)


Purpose. The hydrochloride salts of the N, N-dimethylglycine esters of menahydroquinone-4 (1-mono, 1; 4-mono, 2; and 1,4-bis, 3) were assessed in vivo as prodrug for the systemic site-specific delivery system of menahydroquinone-4 (MKH), the active form of menaquinone-4 (MK-4, vitamin K2(20)). Methods. The disposition of MK-4 and menaquinone-4 epoxide (MKO) following the intravenous administration of the prodrugs and MK-4 preparation solubilized with surfactant (H-MK-4) were studied in vitamin K cycle inhibited rats. The relative bioavailability of MKH after the administration of the prodrugs was assessed from the area under the plasma concentration of MKO vs. time curve (AUCMKO). The specific delivery of MKH to its active site (liver) and coagulation activity after the administration of selected prodrug 1 were then compared with those of H-MK-4 in warfarin poisoned rats. Results. All compounds showed linear pharmacokinetics, and significant bioavailability of MKH was also observed following the administration of 1 (188%), 2 (87%) and 3(135%). Prodrug 1 caused the following increases; AUCliver of MKO from 70.7 ± 5.77 (H-MK-4) to 167 ± 7.89 nmol · h/g, MRTliver of MKO, from 3.87 ± 0.307 to 8.57 ± 0.432 h. The liver accumulation of intrinsic 1 reached a maximum (88% of dose) by 0.25 h. The rapid and liver-selective uptake and liver esterase mediated MKH regeneration characteristics of 1 enhanced the delivery of MKH to its active site and the selective advantage was increased 5.7 fold. The coagulation activity was extended 1.9 fold by 1 administration. Conclusions. The results indicated that these highly water-soluble and liver-esterase hydrolyzable ester derivatives of MKH are potential candidates for parenteral prodrugs which can thus achieve the systemic site-specific delivery of MKH. Such effective and selective delivery of MKH to its active site can therefore lead to enhanced pharmacological efficacy and can also avoid the toxicity induced by the solubilizing agent used in the H-MK-4 preparation.

Original languageEnglish
Pages (from-to)1973-1979
Number of pages7
JournalPharmaceutical Research: An Official Journal of the American Association of Pharmaceutical Scientists
Issue number12
Publication statusPublished - Dec 1995
Externally publishedYes


  • bioavailability
  • coagulation activity
  • menahydroquinone-4
  • site-specific delivery
  • water-soluble prodrug

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)


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