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HERBAL MEDICINE |
From the Department of Clinical Pharmacology (Dr. Yasui-Furukori, Dr. Tateishi) and Neuropsychiatry (Dr. Yasui-Furukori, Dr. Furukori, A. Kaneda, Dr. Kaneko), Hirosaki University School of Medicine, Hirosaki, Japan, and the Department of Psychiatry, Koroishi-Akebono Hospital, Kuroishi, Japan (Dr. Furukori, A. Kaneda).
Address for reprints: Norio Yasui-Furukori, MD, PhD, Department of Clinical Pharmacology, Hirosaki University, School of Medicine, Hirosaki 036-8562, Japan.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Donepezil • Ginkgo biloba • pharmacokinetics • pharmacodynamics • drug-herb interaction • Alzheimer's disease
Ginkgo is derived from the leaf of Ginkgo biloba.It has been used for cognitive disorders, peripheral vascular disease, age-related macular degeneration, vertigo, tinnitus, erectile dysfunction, and altitude sickness.5,6 Several studies suggest that ginkgo may stabilize or improve cognitive performance in patients with Alzheimer's disease and multi-infarct dementia.7-9
Although ginkgo is frequently administered with donepezil in patients with Alzheimer's disease or multi-infarct dementia based on these findings,10 there is no information about a drug interaction between donepezil and ginkgo. Thus, we examined the effect of the extract of Ginkgo biloba on the pharmacokinetics and pharmacodynamics of donepezil in elderly patients with Alzheimer's disease.
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METHODS |
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Study Design
The patients received an oral 5-mg dose of donepezil once a day (8 p.m.) for at least 20 weeks. After no fluctuation of mental status for 28 days was confirmed, ginkgo 90 mg/day (Ichoha Sainoshin, Aihoupu Co., Kagoshima, Japan) was also administrated for 30 days. Concomitant medications were fixed without dosage adjustment during the study period. Blood samplings (16 mL each) for the plasma concentration of donepezil and cholinesterase in red blood cells were taken into heparinized tubes 12 hours after donepezil dosing (8 a.m.), which was performed before and during ginkgo supplementation and 30 days after its discontinuation. Then, 10 mL of blood was separated to plasma immediately, and the plasma was stored at -30°C until analysis. The remaining 6 mL of whole blood was transferred to the laboratory of Sumikin Biosciences Co. (Sagamihara, Kanagawa, Japan) to determine cholinesterase activity in red blood cells. On each day of blood sampling during the protocol, cognitive function was evaluated using the Mini-Mental Scale Examination (MMSE). A rater was blind to the protocol or regimen of each patient.
Assay
The plasma concentration of donepezil was quantified using high-performance liquid chromatography (HPLC) developed in our laboratory.11 The limit of determination of donepezil was 1.5 ng/mL, and the coefficient of variation (CV) was less than 5%. Cholinesterase activity in red blood cells was determined using Ellman methods with spectroscopy.12
Statistical Analysis
Statistical analyses were performed by using Friedman rank tests with SPSS software. All tests were two-tailed and considered to be statistically significant when the p-value was less than 0.05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Galluzzi et al15 have reported a case in which a patient with Alzheimer's disease fell into a coma after taking a combination of ginkgo and trazodone. Ginkgo flavonoids increase the production of 1-(m-chlorophenyl)piperazine (m-CPP), an active metabolite of trazodone, which, by acting on benzodiazepine binding sites, releases 
-aminobutyric acid (GABA) through an agonistic action on presynaptic serotonin 5-HT2 and 
2-adrenergic receptors/located GABAergic activity. Our previous study reported that carbamazepine, an inducer of CYP3A4, decreased the steady-state plasma concentration of trazodone, suggesting the involvement of CYP3A4 in the metabolism of trazodone.16 Thus, it is possible that ginkgo has an inducing effect on CYP3A4 as well as another flavonoid, St. John's wort.17,18 In addition, a recent animal study has shown that the feeding of ginkgo markedly increases the CYP content and CYP2B and CYP3A mRNA in liver.19 Therefore, we presumed that ginkgo supplementation with donepezil would cause some drug interaction.
The results of this study, however, showed that ginkgo did not alter the steady-state plasma concentration of donepezil, which means that ginkgo does not have an inhibitory or inducing effect on the metabolism of donepezil. A recent pharmacokinetic study has shown that ginkgo supplementation did not affect the single point ratios of 1'-hydroxymidazolam/midazolam and debrisoquine urinary recovery ratios, which are regarded as a simple index of CYP3A4 and CYP2D6, respectively.18 These findings support our conclusion that ginkgo does not have any effect on the metabolism of donepezil catalyzed by CYP2D6 and CYP3A4. In the clinical situation, therefore, little concern about the pharmacokinetic interaction between donepezil and ginkgo is needed in the treatment of Alzheimer's disease.
It should be noted that the current study did not measure acetylcholinesterase and pseudocholinesterase separately but just cholinesterase (sum of acetyl- and pseudocholinesterase). Pseudocholinesterase is mainly located in plasma, while acetylcholinesterase is located in red blood cells, to a considerable extent. Therefore, cholinesterase activity in red blood cells is regarded to be roughly reflected by acetylcholinesterase activity. In the present study, cholinesterase in red blood cells was significantly elevated during ginkgo supplementation, although it was a small difference. These findings are in discord with our observation that no change in the pharmacokinetics of donepezil was seen in light of the significant correlation between the plasma concentration of donepezil and the percentage of acetylcholinesterase inhibition.4 Ginkgo itself may have some effects on cholinesterase activity.
Several studies demonstrated that ginkgo itself improves cognitive impairment or memory loss.6-9 However, although ginkgo increased cholinesterase activity in this study, ginkgo supplementation did not alter MMSE scores. A plausible explanation for this discrepancy may be our shorter additional treatment (30 days) than previous reports or that patients with extremely severe Alzheimer's disease (0 points in MMSE scores in 4 patients throughout the study period) were included in this study.
In conclusion, ginkgo supplementation does not have major impact on the pharmacokinetics and pharmacodynamics of donepezil. There was no indication in this study of any adverse drug-herb interaction between donepezil and ginkgo during their combined use in the treatment of Alzheimer's disease.
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FOOTNOTES |
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This study is supported by a grant from the Japanese Research Foundation for Clinical Pharmacology and the Hirosaki Research Foundation for Neurosciences.
Submitted for publication March 15, 2003; Revised version accepted February 8, 2004.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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