Identification of the active components in Shenmai injection that differentially affect Cyp3a4-mediated 1'-hydroxylation and 4-hydroxylation of midazolam.

Abstract

Shenmai injection (SMI) is a popular herbal preparation that is widely used for the treatment of atherosclerotic coronary heart disease and viral myocarditis. In our previous study, SMI was shown to differentially affect CYP3A4-mediated 1'-hydroxylation and 4-hydroxylation of midazolam (MDZ). The present study was conducted to identify the active components in SMI responsible for the differential effects on MDZ metabolism, using in vitro incubation systems (rat and human liver microsomes and a recombinant CYP3A4 system) to measure 1'-hydroxylation and 4-hydroxylation of MDZ. First, different fractions of SMI were obtained by gradient elution on an solid phase extraction system and individually tested for their effects on MDZ metabolism. The results demonstrated that lipid-soluble constituents were likely to be the predominant active components of SMI. Second, the possible active components were gradually separated on an high-performance liquid chromatography system under different conditions and individually tested in vitro for their effects on MDZ metabolism. Third, the active component obtained in the above experiment was collected and subjected to structural analysis, and identified as panaxytriol (PXT). Finally, it was validated that PXT had significant differential effects on 1'-hydroxylation and 4-hydroxylation of MDZ in various in vitro systems that were similar to those of SMI. We conclude that PXT is the constituent of SMI responsible for the differential effects on CYP3A4-mediated 1'-hydroxylation and 4-hydroxylation of MDZ.

• Authors: Caiwen Zeng, Fang He, Chunhua Xia, Hong Zhang, Yuqing Xiong
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 41 Issue 4 Pg. 785-90 (Apr 2013) ISSN: 1521-009X [Electronic] United States
• PMID: 23340957 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Drug Combinations
• Drugs, Chinese Herbal
• Enediynes
• Fatty Alcohols
• Plant Extracts
• fructus schizandrae, radix ginseng, radix ophiopogonis drug combination
• panaxytriol
• Cytochrome P-450 CYP3A
• Midazolam

Topics

• Animals
• Cytochrome P-450 CYP3A (metabolism)
• Drug Combinations
• Drugs, Chinese Herbal (administration & dosage, chemistry)
• Enediynes (analysis, pharmacology)
• Fatty Alcohols (analysis, pharmacology)
• Herb-Drug Interactions
• Humans
• Hydroxylation (drug effects)
• In Vitro Techniques
• Injections
• Microsomes, Liver (drug effects, metabolism)
• Midazolam (chemistry, metabolism, pharmacokinetics)
• Plant Extracts (chemistry, pharmacology)
• Rats