Effects of Individual Ginsenosides, Ginkgolides and Flavonoids on Cyp2c19 and Cyp2d6 Activity in Human Liver Microsomes

Abstract

1. The effects of four individual ginsenosides (Rb1, Rb2, Rc and Rd), two ginkgolides (A and B) and one flavonoid (quercetin) on CYP2C19-dependent S-mephenytoin 4 cent-hydroxylation and CYP2D6-mediated bufuralol 1 cent-hydroxylation were evaluated in human liver microsomes. 2. Increasing concentrations of each test compound were added to microsomal incubation mixtures containing a well-characterized marker substrate (S-mephenytoin for CYP2C19 or bufuralol for CYP2D6) to determine their IC(50) values (compound concentration yielding 50% inhibition of a marker enzyme activity), which were estimated by graphical inspection. 3. For CYP2C19, the IC(50) values were 46, 46 and 62 micromol/L for ginsenoside Rd, quercetin and ginsenoside Rb2, respectively, whereas only ginsenoside Rd had an IC(50) value of 57 micromol/L for CYP2D6. 4. The data suggest that the tested compounds are not likely to inhibit the metabolism of the concurrent use of a given drug whose primary route of elimination is through CYP2C19 or CYP2D6.

Structure-Activity Relationship and Substrate-Dependent Phenomena in Effects of Ginsenosides on Activities of Drug-Metabolizing P450 Enzymes

“…effects of Rd and Rb 2 on CYP2C19 [7], [8]) and conflicts between our data and previous reports (e.g. effects of saponins on several P450s [10]) on the inhibition of P450s by ginsenosides can most likely be attributed to the different substrates and assay systems used to determine the P450 activities.…”

“…For instance, ginsenoside Rd weakly inhibits CYP3A4 and CYP2D6 and inhibit CYP2C19 and CYP2C9 to an even lesser extent; and ginsenosides Rb 1 , Rb 2 , Re, and Rg 1 do not significantly affect CYP1A2, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 [7]. In another study, however, ginsenosides Rd and Rb 2 inhibited CYP2C19-dependent S-mephenytoin 4′-hydroxylation and Rd inhibited CYP2D6-mediated bufuralol 1′-hydroxylation [8]. Moreover, standardized Panax ginseng and Panax quinquefolius extracts decrease the 7-ethoxyresorufin O-dealkylation activities of human CYP1A1, CYP1A2, and CYP1B1, but ginsenosides Rb 1 , Rb 2 , Rc, Rd, Re, Rf or Rg 1 have no significant effects [9].…”

Induction of Cyp3a in Primary Cultures of Human Hepatocytes by Ginkgolides a and B

“…In previous animal studies, rats were fed a GBE‐containing diet or received GBE by intragastric gavage and their hepatic CYP3A mRNA expression 5,13 and enzyme activity 4,6,7,13,17 were markedly increased in a dose‐ and time‐dependent manner. More importantly, there have been studies showing that the different chemical constituents present in the G. biloba may exhibit distinct roles in the regulation of the expression and function of drug‐metabolizing genes 13,18,19 . Similar to St John's wort, 20 different components of the GBE mixture may be responsible for different aspects of its action.…”

Pharmacokinetic Herb-Drug Interactions (Part 2): Drug Interactions Involving Popular Botanical Dietary Supplements and Their Clinical Relevance

“…It is now clear that highly polar, extensively glycosylated ginsenosides (e.g., Rb1, Rb3, Rg3, Re, Rg1, Rg2) are relatively weak modulators of human XMEs and transporters [37,120,[200][201][202][203][204][205][206][207]. Ginsenoside concentrations necessary to inhibit most CYPs and transporters in vitro are not only high (> 50 µM), but are not likely to be realized in vivo, especially if normal dosing recommendations of ginseng products are followed [37,120,127,[200][201][202][203][204][205][206][207]. This also holds true for the even higher ginsenoside concentrations (> 100 µM) required for inducing CYP1A1 [208], CYP2C9, and CYP3A4 [200] activity in human liver cells and microsomes.…”