Identification of ginkgolide B metabolites in urine and rat liver cytochrome P450 enzymes responsible for their formation in vitro.
OBJECTIVE
To identify metabolites of ginkgolide B in rat urine, the predominant metabolism of ginkgolide B and the major cytochrome (CYP) P450 enzymes responsible for the metabolism of ginkgolide B in rat liver microsomes.


METHODS
A liquid chromatography quadrupole mass spectrometer and liquid chromatography ion-trap-time-of-flight mass spectrometer with electrospray ionization in negative-ion mode were used for the structure elucidation of metabolites in rat urine and liver microsome incubation. Various selective CYP450 inhibitors were applied to investigate their effects on the metabolism of ginkgolide B and the formation of the major metabolite in rat liver microsomes.


RESULTS
Three metabolites were identified in rat urine. One hydroxyl metabolite of ginkgolide B were identified in rat liver microsomes, and quinidine uncompetitively inhibited the formation of the metabolite; its inhibitor constant (Ki) value for the inhibition of hydroxyl metabolite was estimated to be 8 micromol/L, while alpha-naphthoflavone, ketoconazole, sulfaphenazole, and diethyldithiocarbamate had no inhibitory effects.


CONCLUSIONS
Ginkgolide B was metabolized to its hydroxyl metabolite in rats, and CYP2D6 was the major rat CYP isoform responsible for the ginkgolide B metabolism in rat liver microsomes.
Wang
Dian-lei
DL
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Liang
Yan
Y
Chen
Wei-dong
WD
Xie
Lin
L
Wang
Guang-ji
GJ
Liu
Xiao-dong
XD
D000818:Animals; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005215:Fasting; D005260:Female; D005343:Fibrinolytic Agents / Q000652:urine*; D046934:Ginkgolides / Q000737:chemistry / Q000378:metabolism / Q000652:urine*; D007783:Lactones / Q000737:chemistry / Q000378:metabolism / Q000652:urine*; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley
D005343:Fibrinolytic Agents; D046934:Ginkgolides; D007783:Lactones; D003577:Cytochrome P-450 Enzyme System; C045856:ginkgolide B; D019389:Cytochrome P-450 CYP2D6