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DRUG METABOLISM

Ginkgo biloba Does Not Alter Clearance of Flurbiprofen, a Cytochrome P450-2C9 Substrate

David J. Greenblatt, Lisa L. von Moltke, Yan Luo, Elke S. Perloff, Kelly A. Horan, Allison Bruce, Robyn C. Reynolds, Jerold S. Harmatz, Bharathi Avula, Ikhlas A. Khan and Peter Goldman

From the Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts–New England Medical Center, Boston, Massachusetts (D. J. Greenblatt, L. L. von Moltke, Y. Luo, E. S. Perloff, K. A. Horan, A. Bruce, R. C. Reynolds, J. S. Harmatz); the National Center for Natural Products Research, University of Mississippi School of Pharmacy (B. Avula, I. A. Khan); and the Division for Research and Education in Complementary and Integrated Medical Therapies, Osher Institute, Harvard Medical School, Boston, Massachusetts (P. Goldman).

Address for reprints: David J. Greenblatt, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111.


   ABSTRACT
TOP
 ABSTRACT
METHODS: CLINICAL STUDY
 METHODS: CONTENT ANALYSIS OF...
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The effect of Ginkgo biloba on the activity of CYP2C9, the isoform responsible for S-warfarin clearance, was assessed in 11 healthy volunteers who received single 100-mg doses of flurbiprofen, a probe substrate for CYP2C9. Subjects also received either a standardized G biloba leaf preparation (Ginkgold, 3 doses of 120 mg) or matching placebo in a randomized, double-blind, 2-way crossover study. Mean kinetic variables for flurbiprofen with either placebo or G biloba were elimination half-life, 3.9 versus 3.5 hours; total AUC, 57 versus 55 µg/mL h; and oral clearance, 32.9 versus 31.6 mL/min. None of these differences was significant. Based on highperformance liquid chromatography analysis, each 60-mg Ginkgold tablet contained 6.6 µg of amentoflavone and 61.2 µg of quercetin, both previously identified as CYP2C9 inhibitors. These amounts were apparently too low to inhibit CYP2C9 function in vivo. The results confirm previous controlled clinical studies showing no effect of ginkgo on the kinetics or dynamics of warfarin.

Key Words: Ginkgo biloba • cytochrome P450-2C9 • flurbiprofen kinetics • herbal products • drug interactions

Widespread use of herbal medicines has led to an increasing number of reports suggesting possible serious interactions with conventional drugs.1-7 Several case reports describe hemorrhagic events in individuals taking preparations of Ginkgo biloba,8-10 perhaps related to the finding that 1 or more components of ginkgo inhibits platelet aggregation. It is also possible, however, that some preparations of ginkgo contain ingredients that enhance the antithrombotic effect of warfarin.10 Since S-warfarin, the pharmacologically active enantiomer of warfarin, is metabolized by cytochrome P450-2C9 (CYP2C9),11,12 hemorrhagic events in patients taking both warfarin and ginkgo could in principle result from impaired CYP2C9-mediated metabolism of warfarin and hence excessive anticoagulation.

Hydroxylation of the nonsteroidal anti-inflammatory drug (NSAID) flurbiprofen is known to be mediated by CYP2C9. Biotransformation of flurbiprofen, often used as a measure of CYP2C9 activity, is inhibited by several components of G biloba when studied with in vitro preparations of human liver microsomes.13,14 Inhibitors described include amentoflavone, quercetin, and sesamin, as well as the newly identified compounds (Z,Z)-4,4'-(1,4-pentadiene-1,5-diyl)diphenol (abbreviated GA-1) and 3-nonadec-8-enyl-benzen-1,2-diol (abbreviated GA-3).14 Of these, the most potent inhibitor is amentoflavone, with a mean 50% inhibitory concentration (IC50) of 35 nM (19 ng/mL), a result consistent with the observation of Gaudineau et al that the flavonoid fraction of ginkgo is a strong inhibitor of CYP2C9.15

The clinical importance of these in vitro results, however, remains uncertain. A clinical study in warfarintreated patients showed no change in anticoagulant control during 4 weeks of exposure to a Danish preparation of ginkgo.16 A study in healthy volunteers showed no effect of an Australian gingko preparation (containing the same standardized dry extract as used in the present study), administered for 7 days, on the kinetics and antithrombotic effect of a single dose of warfarin.17 In other studies involving human subjects18 and aged rats,19 extended ingestion of ginkgo appeared to enhance the clearance of tolbutamide, also metabolized by CYP2C9, suggesting that the herb may be an inducer of this cytochrome.

Since flurbiprofen has been found safe in clinical practice, is metabolized almost exclusively by CYP2C9 in humans to yield 4'-OH-flurbiprofen,20 and can be quantitated by high-performance liquid chromatography (HPLC), it has been used in clinical as well as in vitro studies to monitor the role of CYP2C9 activity.14,20-23 As a result, CYP2C9 has been shown to have diminished activity during aging,24 to be influenced by genetic polymorphism,25 and to be the basis for a number of drug interactions.26 The present study evaluated the effect of short-term exposure to a fixed amount of a standardized preparation of G biloba27 on the kinetics of a single dose of flurbiprofen in human volunteers.


   METHODS: CLINICAL STUDY
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 ABSTRACT
 METHODS: CLINICAL STUDY
METHODS: CONTENT ANALYSIS OF...
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects and Procedures
The study protocol and consent form were reviewed and approved by the institutional review boards at both the Tufts University School of Medicine/Tufts–New England Medical Center (the Human Investigation Review Committee) and the Harvard Medical School.

The study subjects were 12 healthy, ambulatory volunteers aged 19 to 40 years (8 men and 4 women), who were taking no other medication. All gave written informed consent before participating in this single-dose, 2-way crossover study; there was at least a 1-week interval between the study's 2 phases. Subjects were randomized with respect to the order of the following 2 phases:

Flurbiprofen (NSAID, The Upjohn Co) was administered as a 100-mg tablet. G biloba was administered as 60-mg tablets, which had been encapsulated in blue opaque capsules that matched those containing the study placebo (sucrose). The capsules used disintegrated completely within 30 seconds at 37°C in 0.1 N HCl.

Subjects arrived at the Clinical Psychopharmacology Research Unit, Tufts University School of Medicine, at 8 AM on the morning before the administration of flurbiprofen. A single 120-mg dose (2 tablets) of ginkgo (or matching placebo) was administered with tap water. Subjects were provided with another 120-mg dose of ginkgo (or placebo) and instructed to take this dose at 8 PM on the same day.

The following morning, subjects arrived at 7:30 AM in the study unit, were provided a light breakfast, and had an indwelling intravenous catheter placed in a forearm vein. At 8 AM, a third dose of ginkgo (or placebo) was administered. At 8:30 AM, subjects took an oral dose of flurbiprofen (100 mg) with 240 mL of tap water.

Venous blood samples were drawn into heparinized tubes prior to flurbiprofen dosage and again 0.5, 1.0, 1.5, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours thereafter. The blood samples were centrifuged and the plasma separated and frozen at –20°C until the time of assay.

Subjects were provided midday and evening meals at approximately noon and 6 PM and discharged from the study unit after the 12-hour blood sample was taken.

Analysis of Plasma Samples
Chemicals and reagents were obtained from commercial sources. The internal standard, naproxen (25 µg), was added to study sample tubes and, for calibration, to a series of tubes also containing flurbiprofen in quantities ranging from 0.01 to 4.0 µg. Drug-free control serum (0.1 mL) was added to calibration tubes; study sample plasma (0.1 mL) was added to tubes containing only internal standard. Study samples and calibration standards were acidified with 0.2 mL of 2.5 M phosphoric acid and extracted with 2.5 mL of a mixture of hexane and isoamyl alcohol (98.5:1.5, v/v). After vortex mixing in the upright position for 3 minutes, the phases were separated by centrifugation (10 minutes at 200 g). The organic layer was separated, evaporated to dryness in vacuo at 40°C, and then reconstituted with 0.2 mL of chromatographic mobile phase for analysis. The high-performance liquid chromatograph (Waters Associates, Milford, Mass) consisted of a solventdelivery system, autosampler, fluorescence detector, and data-processing system. The mobile phase was 65% 0.02 M KH2PO4 (pH 3.0)/35% acetonitrile, at a flow rate of 1.2 mL/min. The column was C-18 Novapak (4.6-mm diameter, 15-cm length). The fluorescence detector was set at 260 nm for excitation and 320 nm for emission.

Approximate chromatographic retention times were naproxen, 14.5 minutes; flurbiprofen, 6.0 minutes; and 3.4 minutes for what was presumptively 4-OH-flurbiprofen. Because a pure reference standard of 4-OH-flurbiprofen was not available, the retention time of this metabolite was assumed to be that of a metabolite formed during previous studies of flurbiprofen metabolism in vitro21; quantitation of 4-OH-flurbiprofen was done on the assumption that it had the same calibration characteristics as flurbiprofen.

The sensitivity limit for the method is approximately 0.1 µg/mL flurbiprofen for a 0.1-mL plasma sample. The within-day coefficients of variation (CVs) for replicate samples containing 0.15, 1.5, and 15.0 µg/mL were 2.4%, 3.0%, and 3.4%, respectively. Frozen quality control (QC) samples were analyzed along with each analytical run to assess between-day variance. For 10 analytical runs, the QC samples containing 0.15 µg/mL flurbiprofen had a mean measured concentration of 0.15 µg/mL and a CV of 3.1%. For the 1.5-µg/mL and 15.0 µg/mL QC samples, the mean measured concentrations were 1.5 µg/mL and 14.7 µg/mL, respectively, and the CVs were 2.7% and 2.8%. The 10 calibration curves had slopes with a CV of 8.1%.

Kinetic and Statistical Analysis
The terminal log-linear phase of the flurbiprofen concentration curve was identified visually, and the terminal slope was calculated by linear regression. This was used to determine the elimination half-life (t1/2). Area under the curve up to the final detectable plasma concentration was calculated using the linear trapezoidal method. Total area under the plasma concentration curve (AUC) was considered to be the sum of this figure and the residual area extrapolated to infinity, which was estimated as the final concentration divided by the terminal slope. Apparent oral clearance of flurbiprofen was calculated as the administered dose (100 mg) divided by total AUC. Because 4-OH-flurbiprofen concentrations in samples were much lower than those of the parent compound, comparable estimates for this metabolite were based only on the AUC up to the final detectable concentration.

Student's paired t test was used to compare results obtained on each subject after exposure to ginkgo and placebo for both flurbiprofen (AUC, clearance, halflife, and maximum plasma concentration [Cmax]) and 4-OH-flurbiprofen (truncated AUC). A value of P < .05 was taken as the criterion for statistical significance.


   METHODS: CONTENT ANALYSIS OF GINKGO TABLETS
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 ABSTRACT
 METHODS: CLINICAL STUDY
 METHODS: CONTENT ANALYSIS OF...
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Chemicals and Materials
HPLC-grade acetonitrile and acetic acid were purchased from Fisher Scientific (Fair Lawn, NJ). Water for the HPLC mobile phase was purified in a Milli-Q system (Millipore, Bedford, Mass). Quercetin and sesamin were purchased from Sigma (St. Louis, MO). Amentoflavone was isolated and GA-1 was synthesized at the National Center for Natural Products Research, University of Mississippi13,14 Their identity and purity were confirmed by chromatographic (thin-layer chromatography, HPLC) methods and comparison with published spectral data (infrared, nuclear magnetic resonance, and high-resolution mass spectroscopy).

Sample Preparation
The finely powdered constituents of 3 Ginkgold tablets were sonicated in 2.5 mL of methanol for 15 minutes followed by centrifugation for 10 minutes at 3300 rpm. The supernatant was transferred to a 10.0-mL volumetric flask. The procedure was repeated 3 times, and respective supernatants were combined. The final volume was adjusted to 10 mL with methanol. Prior to use, all samples were filtered through a 0.45-µm nylon membrane filter.

HPLC Parameters
Analysis was performed on an Alliance 2695 separation module with 996 photodiode array detection and Millennium-32 software package (Waters Corp, Milford, Mass) using a Phenomenex Gemini C18 column (150 x 4.6 mm, 5 µ particle size) from Phenomenex (Torrance, Calif). The mobile phase consisted of water (0.1% acetic acid) (A) and acetonitrile (0.1% acetic acid) (B) at a flow rate of 1.0 mL/min and a temperature of 30°C. The gradient elution was as follows: 95A/5B to 20A/80B in 25 minutes, then to 100B in 2 minutes, next 15 minutes 100% B. After the injection of 10 µL, the data were collected and analyzed by Waters Millennium-32 software (Milford, Mass).


   RESULTS
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 METHODS: CLINICAL STUDY
 METHODS: CONTENT ANALYSIS OF...
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DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Clinical Study
Data from 1 of the 12 subjects could not be used because the subject did not adhere to the protocol. Among the remaining 11 participants, 1 (a 40-year-old white man) had a very long t1/2 (8.3-8.7 hours) and a low clearance of flurbiprofen (7.6-8.0 mL/min) in both phases of the trial as compared to the 10 other adherent subjects. The metabolite, 4-OH-flurbiprofen, was not detected in this subject's plasma in either phase of the study. He apparently had a CYP2C9 "poor metabolizer" genotype, a possibility that we did not further investigate. Nevertheless, among the 11 subjects analyzed, there was no significant difference between ginkgo or placebo treatment in any of flurbiprofen's kinetic variables, whether or not the analysis included the individual with unusually low clearance (Table I; Figure 1). The metabolite 4-OH-flurbiprofen apparently was formed in concentrations considerably lower than the parent drug for all subjects (Figure 2), and ginkgo appeared to have no effect on 4-OH-flurbiprofen's truncated AUC (Table I).


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  		Table I Effect of Ginkgo biloba Coadministration on the Pharmacokinetics of Flurbiprofen

 

Figure 1
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  		Figure 1. Mean (SE, n = 10) plasma flurbiprofen concentrations following a single 100-mg dose of flurbiprofen during cotreatment with placebo or with ginkgo. (Top) Linear scale. (Bottom) Logarithmic scale. The individual described in the text is not included in this analysis.

 

Figure 2
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  		Figure 2. Mean (SE, n = 10) plasma concentrations of 4-OH-flurbiprofen following a single 100-mg dose of flurbiprofen during cotreatment with placebo or with ginkgo. The individual described in the text is not included in the analysis.

 

Content Analysis
A 60-mg tablet of Ginkgold was found to contain 61 µg of quercetin and 6.6 µg of amentoflavone (Figure 3). Sesamin and GA-1 were not detected.


Figure 3
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  		Figure 3. (Top) Chromatogram (280 nm) of a standard mixture of quercetin (1), amentoflavone (2), sesamin (3), GA-1 (4). (Bottom) Chromatogram of an extract of Ginkgold tablets.

 

   DISCUSSION
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 ABSTRACT
 METHODS: CLINICAL STUDY
 METHODS: CONTENT ANALYSIS OF...
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
Pretreatment of healthy volunteers with usual clinical doses of a standardized G biloba preparation27 has no detectable effect on the pharmacokinetics of a single dose of flurbiprofen or on the apparent extent of formation of the principal hydroxylated metabolite. The findings suggest that short-term exposure to G biloba does not inhibit CYP2C9 activity. Despite anecdotal (and unvalidated) reports of enhanced anticoagulation in warfarin-treated patients who concurrently take ginkgo,10 it is not likely to result from a CYP2C9-mediated pharmacokinetic interaction between a ginkgo component and the pharmacologically active S-enantiomer of warfarin. Thus, our findings are consistent with previous results16,17 demonstrating no change in warfarin's anticoagulant effect in patients or volunteers also receiving ginkgo, although with more extended exposure. Our study involved only short-term exposure to G biloba and therefore would not have demonstrated a small inductive effect previously suggested18 based on a reduced hypoglycemic effect of tolbutamide (primarily a CYP2C9 substrate)22,23 with 7 days of exposure to ginkgo. An inductive effect would, in principle, inhibit the anticoagulant effect of warfarin, which has not been reported, perhaps because the clinical consequences are less dramatic. Finally, this study did not address potential antithrombotic effects of ginkgo occurring via other mechanisms such as alterations of platelet function.28

In vitro studies from our laboratory14 and others15 have indicated significant CYP2C9 inhibitory properties of the flavonoid or biflavone components of G biloba.29,30 This property appears limited to the flavonol aglycones, with the glycoside derivatives having little inhibitory effect. Thus, the biflavone aglycone amentoflavone is a highly potent inhibitor, whose in vitro IC50 for flurbiprofen hydroxylation is 19 ng/mL (35 nM). Content analysis of the ginkgo preparation indicated that each tablet contained 6.6 µg of amentoflavone. This quantity evidently is insufficient to cause CYP2C9 inhibition in vivo. It is also possible that amentoflavone, like other flavonoid aglycones, is glucuronide conjugated prior to reaching the liver, in which form it is no longer inhibitory for CYP2C9.31 The apparent paradox underscores the need for caution in extrapolating in vitro metabolic findings on natural products to the clinical situation.

There is another limitation to this and other studies that provide pharmacological and clinical data about herbs. Although such studies seem to be the counterpart of those on which decisions about conventional drugs are based, there are crucial differences between herbs and conventional drugs that must be considered. The biggest difference is that conventional drugs have chemically defined ingredients and are formulated to have consistent bioavailability, whereas herbs contain many ingredients including some that are not chemically defined. The contents of such ingredients, which may have either desired or undesired pharmacological activity, like many plant components, are known to be affected by where the plant is grown and how it is stored and extracted to provide the preparation that is actually consumed.1

This uncertainty about the composition of herbs and hence the consistency of their pharmacological properties adds uncertainties not found with conventional drugs. We have done our best to limit these uncertainties in this study by using the patented formulation of ginkgo, EGb 761, which should be more consistent than other ginkgo products because it is said to be made from ginkgo plants grown, harvested, and extracted under standardized conditions and formulated to several defined chemical standards.27 We have also documented the content of constituents that might be implicated in a clinical interaction with substrates of CYP2C9. Nevertheless, our results are not necessarily applicable to all ginkgo products currently available to the public.

Thus, we are faced with a vexing problem with regard to possible drug interactions with ginkgo and other herbal products now being marketed in the United States. First, there is the challenge of deciding whether an adverse clinical event to a chemically defined drug is a reaction to the drug.32,33 In the case of herbs, however, the challenge is greater because of the additional uncertainty of the chemical composition and hence the pharmacological properties of the herbal preparation to which the patient was actually exposed, a point often neglected when adverse reactions to herbs are reported and discussed.


   ACKNOWLEDGEMENTS
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 ABSTRACT
 METHODS: CLINICAL STUDY
 METHODS: CONTENT ANALYSIS OF...
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
This work was supported in part by grants AT-00607, AT-01381, MH-58435, DA-13209, DK/AI-58496, DA-13834, AG-17880, AI-58784, and RR-00054 from the Department of Health and Human Services. We are grateful for the assistance of Brian M. DeCicco and Cyrus Wong.

DOI: 10.1177/0091270005283465


   REFERENCES
TOP
 ABSTRACT
 METHODS: CLINICAL STUDY
 METHODS: CONTENT ANALYSIS OF...
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

1. Goldman P. Herbal medicines today and the roots of modern pharmacology. AnnInternMed. 2001;135: 594-600.[Abstract/Free Full Text]

2. Greenblatt DJ, von Moltke LL. Interaction of warfarin with drugs, natural substances, and foods. J Clin Pharmacol. 2005;45: 127-132.[Abstract/Free Full Text]

3. De Smet PA. Herbal remedies. N Engl J Med. 2002;347: 2046-2056.[Free Full Text]

4. Valli G, Giardina EG. Benefits, adverse effects and drug interactions of herbal therapies with cardiovascular effects. J Am Coll Cardiol. 2002;39: 1083-1095.[Abstract/Free Full Text]

5. Zhou S, Gao Y, Jiang W, Huang M, Xu A, Paxton JW. Interactions of herbs with cytochrome P450. Drug Metab Rev. 2003;35: 35-98.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

6. Ernst E. The risk-benefit profile of commonly used herbal therapies: ginkgo, St. John's Wort, ginseng, echinacea, saw palmetto, and kava. AnnInternMed. 2002;136: 42-53.[Abstract/Free Full Text]

7. Coxeter PD, McLachlan AJ, Duke CC, Roufogalis BD. Herb-drug interactions: an evidence based approach. Curr Med Chem. 2004;11: 1513-1525.[Web of Science][Medline] [Order article via Infotrieve]

8. Gilbert GJ. Ginkgo biloba. Neurology. 1997;48: 1137.[Web of Science][Medline] [Order article via Infotrieve]

9. Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas associated with chronic Ginkgo biloba ingestion. Neurology. 1996;46: 1775-1776.[Free Full Text]

10. Matthews MK Jr. Association of Ginkgo biloba with intracerebral hemorrhage. Neurology. 1998;50: 1933-1934.[Web of Science][Medline] [Order article via Infotrieve]

11. Yamazaki H, Shimada T. Human liver cytochrome P450 enzymes involved in the 7-hydroxylation of R- and S-warfarin enantiomers. Biochem Pharmacol. 1997;54: 1195-1203.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

12. He M, Kunze KL, Traeger WF. Inhibition of (S)-warfarin metabolism by sulfinpyrazone and its metabolites. Drug Metab Dispos. 1995;23: 659-663.[Abstract]

13. Bedir E, Tatli I, Khan RA, et al. Biologically active secondary metabolites from Ginkgo biloba. J Agric Food Chem. 2002;50: 3150-3155.[CrossRef][Medline] [Order article via Infotrieve]

14. von Moltke LL, Weemhoff JL, Bedir E, et al. Inhibition of human cytochromes P450 by components of Ginkgo biloba. J Pharm Pharmacol. 2004;56: 1039-1044.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

15. Gaudineau C, Beckerman R, Welbourn S, Auclair K. Inhibition of human P450 enzymes by multiple constituents of the Ginkgo biloba extract. Biochem Biophys Res Commun. 2004;318: 1072-1078.[CrossRef][Medline] [Order article via Infotrieve]

16. Engelsen J, Nielsen JD, Winther K. Effect of coenzyme Q10 and Ginkgo biloba on warfarin dosage in stable, long-term warfarin treated outpatients: a randomised, double blind, placebo-crossover trial. Thromb Haemost. 2002;87: 1075-1076.[Web of Science][Medline] [Order article via Infotrieve]

17. Jiang X, Williams KM, Liauw WS, et al. Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol. 2005;59: 425-432.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

18. Uchida U, Yamada H, Li XD, et al. Effects of Ginkgo biloba on pharmacokinetics and pharmacodynamics of tolbutamide and midazolam. Paper presented at: Eighth World Congress on Clinical Pharmacology and Therapeutics; August 1-6, 2004; Brisbane, Australia.

19. Sugiyama T, Kubota Y, Shinozuka K, Yamada S, Wu J, Umegaki K. Ginkgo biloba extract modifies hypoglycemic action of tolbutamide via hepatic cytochrome P450 mediated mechanism in aged rats. Life Sci. 2004;75: 1113-1122.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

20. Tracy TS, Marra C, Wrighton SA, Gonzalez FJ, Korzekwa KR. Studies of flurbiprofen 4'-hydroxylation: additional evidence suggesting the sole involvement of cytochrome P450 2C9. Biochem Pharmacol. 1996;52: 1305-1309.[CrossRef][Medline] [Order article via Infotrieve]

21. Giancarlo GM, Venkatakrishnan K, Granda BW, von Moltke LL, Greenblatt DJ. Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: inhibition by sulfaphenazole, omeprazole and ticlopidine. Eur J Clin Pharmacol. 2001;57: 31-36.[CrossRef][Medline] [Order article via Infotrieve]

22. Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Human drug metabolism and the cytochromes P450: application and relevance of in vitro models. J Clin Pharmacol. 2001;41: 1149-1179.[Abstract]

23. Venkatakrishnan K, von Moltke LL, Obach RS, Greenblatt DJ. Drug metabolism and drug interactions: application and clinical value of in vitro models. Curr Drug Metab. 2003;4: 423-459.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

24. Lee CR, Pieper JA, Frye RF, Hinderliter AL, Blaisdell JA, Goldstein JA. Differences in flurbiprofen pharmacokinetics between CYP2C9*1/*1, *1/*2, and *1/*3 genotypes. Eur J Clin Pharmacol. 2003;58: 791-794.[Medline] [Order article via Infotrieve]

25. Patel BK, Jackson SH, Swift CG, Hutt AJ. Disposition of flurbiprofen in man: influence of stereochemistry and age. Xenobiotica. 2003;33: 1043-1057.[CrossRef][Medline] [Order article via Infotrieve]

26. Frye RF, Tracy TS, Hutzler JM, et al. Flurbiprofen as a selective in vivo probe of CYP2C9 activity [abstract]. Clin Pharmacol Ther. 2000;67: 109.

27. Christen Y, Maixent JM. What is Ginkgo biloba extract EGb 761? An overview—from molecular biology to clinical medicine. Cell Mol Biol (Noisy-le-grand). 2002;48: 601-611.[Medline] [Order article via Infotrieve]

28. Kudolo GB, Dorsey S, Blodgett J. Effect of the ingestion of Ginkgo biloba extract on platelet aggregation and urinary prostanoid excretion in healthy and type 2 diabetic subjects. Thromb Res. 2002;108: 151-160.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

29. van Beek TA. Chemical analysis of Ginkgo biloba leaves and extracts. J Chromatogr A. 2002;967: 21-55.[Medline] [Order article via Infotrieve]

30. Yu F-C, Lai S-M, Suen S-Y. Extraction of flavonoid glycosides from Ginkgo biloba leaves and their adsorption separations using hydrophobic and anion-exchange membranes. Separation Science and Technology. 2003;38: 1022-1050.

31. Scalbert A, Williamson G. Dietary intake and bioavailability of polyphenols. JNutr. 2000;130: 2073S-2085S.[Abstract/Free Full Text]

32. Kramer MS, Leventhal JM, Hutchinson TA, Feinstein AR. An algorithm for the operational assessment of adverse drug reactions. I. Background, description, and instructions for use. JAMA. 1979;242: 623-632.[Abstract/Free Full Text]

33. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30: 239-245.[Web of Science][Medline] [Order article via Infotrieve]
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