华中科技大学学报(医学)(英德文版)
華中科技大學學報(醫學)(英德文版)
화중과기대학학보(의학)(영덕문판)
JOURNAL OF HUAZHONG UNIVERSITY OF SCIENCE AND TECHNOLOGY(MEDICAL SCIENCE)
2010年
5期
562-568
,共7页
饶子超%斯陆勤%关延彬%潘洪平%裘军%李高
饒子超%斯陸勤%關延彬%潘洪平%裘軍%李高
요자초%사륙근%관연빈%반홍평%구군%리고
midazolam%Cremophor RH40%Tween 80%cytochrome P450 3A%self-microemulsifying drug delivery systems
This study examined the effect of self-microemulsiflying drug delivery system (SMEDDS) containing Cremophor RH40 or Tween 80 at various dilutions on cytochrome P450 3A (CYP3A) enzymes in rat hepatocytes, with midazolam serving as a CYP3A substrate. The particle size and zeta potential of microemulsions were evaluated upon dilution with aqueous medium. In vitro release was detected by a dialysis method in reverse. The effects of SMEDDS at different dilutions and surfactants at different concentrations on the metabolism of MDZ were investigated in murine hepatocytes. The cytotoxicity of SMEDDS at different dilutions was measured by LDH release and MTT technique. The effects of SMEDDS on the CYP3A enzymes activity were determined by Western blotting. Our results showed that dilution had less effect on the particle size and zeta potential in the range from 1:25 to 1:500. The MDZ was completely released in 10 h. A significant decrease in the formation of 1'-OH-MDZ in rat hepatocytes was observed after treatment with both SMEDDS at dilutions ranging from 1:50 to 1:250 and Cremophor RH 40 or Tween 80 at concentrations ranging from 0.1% to 1% (w/v), with no cytotoxicity observed. A significant decrease in CYP3A protein expression was observed in cells by Western blotting in the presence of either Cremophor RH40 or Tween 80-based SMEDDS at the dilutions ranging from 1:50 to 1:250. This study suggested that the excipient inhibitor-based formulation is a potential protective platform for decreasing metabolism of sensitive drugs that are CYP3A substrates.