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Keywords:

  • bioavailability;
  • bufadienolides;
  • lipid microsphere;
  • pharmacokinetics;
  • stability

Abstract

The degradation kinetics in vitro and pharmacokinetics of bufadienolides loaded in lipid microsphere (BU-LM) after intravenous (IV) administration were investigated and compared with bufadienolides solution (BU-S). The bioavailabilities of BU-LM after intraportal (FIP), intraduodenal (FID), and intragastric (FIG) administrations to rats were also evaluated. The degradation kinetics showed that BU-LM could protect bufadienolides from rapid metabolism in the plasma and gastrointestinal tract. The pharmacokinetic study revealed that BU-LM after IV administration exhibited longer half-life, longer mean residence time and higher apparent volume of distribution than intravenous BU-S. After different routes of administration of BU-LM, cinobufagin (C), and resibufogenin (R) were metabolized completely and could not be detected at an oral dose of 6 mg/kg. Furthermore, C exhibited a complete hepatic first-pass effect after IP administration of 0.5 mg/kg BU-LM. Bufalin (B), the lowest component of the BU-LM could be detected at any administration and the FIG, FID, and FIP for B were 43.05, 88.93, and 93.31%, respectively. R had a FID and FIP of only 1.51 and 2.77%, respectively. The results demonstrated that the stomach appeared to be the dominating site of metabolism for B and the liver for C and R.

Practical applications: Bufadienolides, consisting of bufalin (B), binobufagin (C), and resibufogenin (R) are easily hydrolyzed (catalyzed by acids, bases, and enzymes) and are metabolized rapidly in rats because of their chemical structures, especially C. However, the three bufadienolides could be protected from degradation effectively and the degradation half-lives could be extended to different degrees by using lipid microspheres (LM) as a delivery system. Also, after intravenous administration to rats, bufadienolides-loaded lipid microspheres (BU-LM) could slow down the metabolism and elimination of bufadienolides, delay the release and increase the targeted effect of the drug compared with bufadienolides aqueous solution (BU-Siv). Consequently, LM is a promising alternative vehicle for bufadienolides.