In vitro intestinal absorption and first-pass intestinal and hepatic metabolism of cycloastragenol, a potent small molecule telomerase activator.
Cycloastragenol (CAG) is the aglycone derivative of astragaloside IV which has recently been demonstrated to activate telomerase and represents a potential drug candidate for the treatment of degenerative diseases. In the present study, intestinal absorption and metabolism of CAG were examined using the Caco-2 model and liver microsomes, respectively. The results showed that CAG rapidly passes through the Caco-2 cell monolayer by passive diffusion. Four different glucuronide conjugates and two oxidized CAG metabolites were found in the apical and basolateral sides of Caco-2 monolayer, suggesting that first-pass intestinal metabolism of CAG might occur upon passage through the intestinal epithelium. CAG underwent extensive metabolism in rat and human liver microsomes with only 17.4% and 8.2%, respectively, of the starting amount of CAG remaining after 30 min of incubation. Monohydroxylation of the parent and oxidization of the hydroxylated CAG were found in the liver samples. The present study indicates that CAG is efficiently absorbed through intestinal epithelium. However, extensive first-pass hepatic metabolism would limit the oral bioavailability of this compound.
Zhu
Jing
J
Biotechnology Research Institute, Department of Biochemistry, Hong Kong University of Science and Technology, Hong Kong, China.
Lee
Stephanie
S
Ho
Maurice K C
MK
Hu
Yueqing
Y
Pang
Haihong
H
Ip
Fanny C F
FC
Chin
Allison C
AC
Harley
Calvin B
CB
Ip
Nancy Y
NY
Wong
Yung H
YH
D000818:Animals; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D004058:Diffusion / Q000187:drug effects; D004533:Egtazic Acid / Q000494:pharmacology; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism; D020536:Enzyme Activators / Q000378:metabolism*; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D050216:Metabolic Detoxication, Phase I / Q000502:physiology; D050217:Metabolic Detoxication, Phase II / Q000502:physiology; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D010539:Permeability / Q000187:drug effects; D051381:Rats; D012502:Sapogenins / Q000378:metabolism*; D013045:Species Specificity; D021241:Spectrometry, Mass, Electrospray Ionization; D019098:Telomerase; D057900:Transcytosis / Q000187:drug effects / Q000502:physiology
D002352:Carrier Proteins; D020536:Enzyme Activators; D020719:Glucuronides; D012502:Sapogenins; D004533:Egtazic Acid; D019098:Telomerase; C061014:cycloastragenol