Enhanced rectal absorption of amphotericin B lyophilized with glycyrrhizinate in rabbits.
The influence of bases and additives in the formulation for rectal absorption of amphotericin B (AMB) lyophilized with dipotassium glycyrrhizinate (GLYK) was investigated using rabbits in relation to an in vitro release test. The release of AMB from the fatty base of Witepsol or a medium chain triglyceride (MCT) was markedly faster than that from the hydrophilic base of macrogol. The addition of polyoxyethylene (2) lauryl ether (POE(2)LE) into the fatty bases led to a marked increase in the release rate, whereas POE(9)LE or sodium lauryl sulfate resulted in a significantly lower release rate. Animals received rectally each of seven AMB formulations of Witepsol H-15, macrogol, MCT with surfactants and aqueous solution. The absorption of the AMB lyophilized mixture with GLYK at a 1:9 molar ratio from a MCT base was significantly superior to that from macrogol. The addition of POE(2)LE into the MCT base resulted in a marked increase in bioavailability, showing the highest bioavailability of 4.9%. High serum levels of over 100 ng/ml of serum were maintained for 24 h following administration. The lowest bioavailability was 0.32% for the macrogol suppository. There was a good correlation between the release rate of AMB from the formulations and bioavailability. These results suggest that an AMB rectal formulation may provide a promising therapeutic alternative to infusion, taking into account the serum level of AMB exceeding the minimal inhibitory concentration of the infecting organism.
Tanaka
M
M
Kanagawa Laboratories, Bristol-Myers Squibb K.K., Japan.
Kuwahara
E
E
Takahashi
M
M
Koyama
O
O
Takahashi
N
N
Yotsuyanagi
T
T
D000042:Absorption; D000666:Amphotericin B / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage*; D005612:Freeze Drying; D019695:Glycyrrhizic Acid / Q000008:administration & dosage*; D008297:Male; D011817:Rabbits; D012007:Rectum / Q000378:metabolism*; D013488:Suppositories; D013501:Surface-Active Agents / Q000494:pharmacology
D000935:Antifungal Agents; D013488:Suppositories; D013501:Surface-Active Agents; D019695:Glycyrrhizic Acid; D000666:Amphotericin B