Inhibition of Human CYP2B6-Catalyzed Bupropion Hydroxylation by Ginkgo biloba Extract: Effect of Terpene Trilactones and Flavonols

Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, BC, V6T 1Z3, Canada.
Drug metabolism and disposition: the biological fate of chemicals (Impact Factor: 3.25). 07/2009; 37(9):1931-7. DOI: 10.1124/dmd.109.028118
Source: PubMed


Cytochrome P450 2B6 (CYP2B6) is expressed predominantly in human liver. It catalyzes the oxidative biotransformation of various drugs, including bupropion, which is an antidepressant and a tobacco use cessation agent. Serious adverse effects of high dosages of bupropion have been reported, including the onset of seizure. As Ginkgo biloba extract may be consumed with bupropion or another CYP2B6 drug substrate, potential exists for an herb-drug interaction. Therefore, we investigated the effect of G. biloba extract and some of its chemical constituents (terpene trilactones and flavonols) on the in vitro catalytic activity of CYP2B6 as assessed by the bupropion hydroxylation assay with recombinant enzyme and hepatic microsomes. The amount of hydroxybupropion was quantified by a novel and validated ultraperformance liquid chromatography/mass spectrometry method. Enzyme kinetic analysis indicated that G. biloba extract competitively inhibited hepatic microsomal CYP2B6-catalyzed bupropion hydroxylation (apparent K(i) was 162 +/- 14 microg/ml). Bilobalide and ginkgolides A, B, C, and J were not responsible for the inhibition of CYP2B6 catalytic activity by the extract. Whereas the 3-O-glucoside and 3-O-rutinoside of quercetin, kaempferol, and isorhamnetin had no effect, the corresponding aglycones (10 and 50 microg/ml) decreased hepatic microsomal bupropion hydroxylation. The inhibition of CYP2B6 by kaempferol was competitive (apparent K(i) was 10 +/- 1 microg/ml). In summary, G. biloba extract and its flavonol aglycones are naturally occurring inhibitors of in vitro CYP2B6 catalytic activity and bupropion hydroxylation. Future studies are needed to investigate whether G. biloba extract interacts in vivo with bupropion or other clinically important CYP2B6 drug substrates.

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    • "Bupropion 4-hydroxylase activity is a widely used catalytic marker of CYP2B6 activity in human liver microsomes (Faucette et al., 2000; Hesse et al., 2000). Hepatic microsomal bupropion 4-hydroxylase activity was measured using UHPLC/MS/MS analysis as described by Lau and Chang (2009). Reaction mixtures contained human liver microsomes (0.5 mg/ml final concentration), a saturating concentration of bupropion (100µM final concentration), and 50mM phosphate buffer with 3mM magnesium chloride (pH 7.4), in a volume of 0.49 ml. "
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    ABSTRACT: Hydroxylated polybrominated diphenyl ethers (PBDEs) have been found in human serum, suggesting that they are formed by in vivo oxidative metabolism of PBDEs. However, the biotransformation of 2,2',4,4',5-pentabromodiphenyl ether (BDE-99), a major PBDE detected in human tissue and environmental samples, is poorly understood. In the present study, the oxidative metabolism of BDE-99 was assessed using pooled and single-donor human liver microsomes, a panel of human recombinant cytochrome P450 (CYP) enzymes, and CYP-specific antibodies. Hydroxylated metabolites were quantified using a liquid chromatography/tandem mass spectrometry-based method. In total, 10 hydroxylated metabolites of BDE-99 were produced by human liver microsomes. Six metabolites were identified as 2,4,5-tribromophenol (2,4,5-TBP), 4-OH-BDE-90, 5'-OH-BDE-99, 6'-OH-BDE-99, 4'-OH-BDE-101, and 2-OH-BDE-123 using authentic standards. Three monohydroxy- and one dihydroxy-pentabrominated metabolites were unidentified. Rates of formation of the three major metabolites (2,4,5-TBP, 5'-OH-BDE-99, and 4'-OH-BDE-101) by human liver microsomes ranged from 24.4 to 44.8 pmol/min/mg protein. Additional experiments demonstrated that the dihydroxylated metabolite was a primary metabolite of BDE-99 and was not produced by hydroxylation of a monohydroxy metabolite. Among the panel of recombinant CYP enzymes tested, formation of all 10 hydroxylated metabolites was catalyzed solely by CYP2B6. A combined approach using antibodies to CYP2B6 and single-donor liver microsomes expressing a wide range of CYP2B6 levels confirmed that CYP2B6 was responsible for the biotransformation of BDE-99. Collectively, the results show that the oxidative metabolism of BDE-99 by human liver microsomes is catalyzed solely by CYP2B6 and is an important determinant of the toxicity and bioaccumulation of BDE-99 in humans.
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    • "Bupropion ((±)-2-(tert-butylamino)-30-chloropropiophenone hydrochloride) is a second-generation antidepressant agent with neurochemical properties different from common tricyclic antidepressants (Yeniceli and Dogrukol-Ak 2009). It is also used as a non-nicotine drug for smoking cessation (Lau and Chang 2009). Bupropion (BUP) is metabolized to three metabolites: hydroxybupropion (HBUP), erythrohydrobupropion, and threohydroburpropion (Golden et al. 1988; Hesse et al. 2000; Schroeder 1983). "
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    • "However, there was no change in the exposure of lopinavir, likely due to ritonavir's potent inhibition of CYP3A4. Amongst the 7 publications in 2009 [22, 23, 33, 44, 45, 46, 58], 3 revelead the results of studies on the effect of Ginkgo biloba on the efficacy of bupropion and talinolol in humans. Lei et al. [45] studied the interaction between bupropion (150 mg) and Ginkgo biloba 240 mg daily, received orally for 14 days by 14 healthy male volunteers. "
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