Ginkgo biloba extract modifies hypoglycemic action of tolbutamide via hepatic cytochrome P450 mediated mechanism in aged rats.
We examined hepatic cytochrome P450 (CYP)-mediated interactions between Ginkgo biloba extract (GBE) and tolbutamide, an oral anti-diabetic agent, in aged and young rats. Tolbutamide was orally given to rats with or without GBE treatment, and time-dependent changes in blood glucose were monitored. The basal activity of six CYP subtypes in liver was lower in the aged rats than in the young rats, while the inductions of these enzymes by 5 day pretreatment of 0.1% GBE diet were more in the aged rats. Further, the pretreatment of GBE significantly attenuated the hypoglycemic action of tolbutamide in the aged rats, corresponding well to the enhanced activity of (S)-warfarin 7-hydroxylase, which is responsible for CYP2C9 subtype, a major isoform metabolizing tolbutamide. In contrast, the simultaneous administration of GBE with tolbutamide potentiated the hypoglycemic action of this drug. The in vitro experiments revealed that GBE competitively inhibited the metabolism of tolbutamide by (S)-warfarin 7-hydroxylase in the rat liver microsomes. In the young rats, the 5 day pretreatment with GBE significantly attenuated the hypoglycemic action of tolbutamide, but a simultaneous treatment had little influence on the tolbutamide effect. In conclusion, the present study has shown that the simultaneous and continuous intake of GBE significantly affects the hypoglycemic action of tolbutamide, possibly via a hepatic CYP enzyme-mediated mechanism, particularly in the aged rats. Therefore, it is anticipated that the intake of GBE as a dietary supplement with therapeutic drugs should be cautious, particularly in elderly people.
Sugiyama
Tomomi
T
National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjuku, Tokyo 162-8636, Japan.
Kubota
Yoko
Y
Shinozuka
Kazumasa
K
Yamada
Shizuo
S
Wu
Jian
J
Umegaki
Keizo
K
D000704:Analysis of Variance; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D020441:Ginkgo biloba / Q000737:chemistry*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014044:Tolbutamide / Q000378:metabolism*
D001786:Blood Glucose; D010936:Plant Extracts; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases