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MDPI · Pflanze

Ginkgo biloba

Quelle abgerufen

Ginkgo biloba

HOS-368825 · tcm:mdpi-2020-106:ginkgo-biloba

Veröffentlicht / fachlich aktualisiert: 04.07.2020 · Quelle abgerufen: 27.10.2026

Arzneimittelbeziehung · nifedipine

2.1.2. Ginkgo Biloba

Quellenbefund mit unverändertem Untersuchungskontext. Klinischer Schweregrad: nicht bewertet.

2.1.2. Ginkgo Biloba Initially, it has been highlighted in an in vitro cell-based luciferase reporter gene assay that an extract of Ginkgo biloba activates human PXR, in a concentration-dependent manner [71]. This extract included concentrations of ginkgolide A, B, C, and J, bilobalide and flavonols similar to those found in the standardized extract EGb 761 [71]. In particular, G. biloba extract at 200 µg/mL increased by 9.5-fold human PXR activation [71] and the expression of PXR target genes, i.e., CYP3A4, CYP3A5 and ABCB1 (encoding P-gp) in human LS180 colon adenocarcinoma cells [71]. Successively, Li and colleagues [71] confirmed that G. biloba extract (EGb 761, 100 µg/mL) activates human PXR by identifying the constituent/s responsible for this effect [72]. Accordingly, in human HepG2 cells, cell-based reporter assays indicated that ginkgolide A (GA; 50 µM) and ginkgolide B (GB; 50 µM) activate PXR; quercetin (25 µg/mL) and kaempferol (20 µg/mL) activate PXR, CAR, and aryl hydrocarbon receptor (AhR), whereas bilobalide (BB; 50 µM) does not induce effects on these nuclear receptors [72]. In particular, in human primary hepatocytes, it was shown that only EGb 761, GA, and GB were able to induce CYP3A4, CYP2B6, UGTI A1, ABCB1 and MRP2, whereas BB and the flavonoids kaempferol and quercetin were inactive [72]. More recently, molecular docking analysis has showed that the PXR binding energy was great for GA and GB [73]. The authors compared the GA effect with hyperforin, pointing out that the ginkgolide was less powerful (EC50 = 16.2 µM) than hyperforin (EC50 = 0.02–0.2 µM) but both showed similar efficacy (Emax = 11.5 fold for GA vs. 6- to 12-fold for hyperforin) [73]. Specifically, it was documented that the flavonoidic fraction of EGb761 inhibits the enzyme activity of CYP 3A4, 2C9, 1A2, 2El with Ki between 4.9 and 55 microg/mL [74]. Not exhaustive and contrasting data were obtained in vivo after the treatment of rats with G. biloba, where it was shown that the extract increases metabolic [75] and inhibits P-gp activity [76]. The administration of G. biloba extract (100 mg/kg for 5 days) significantly reduced the AUC (0-12) of tolbutamide by 53% in low-protein diet-fed rats and by 38% in normal rats [75]. Conversely, treatment with G. biloba extract for 30 days with a dose of 100 mg/kg increased tissue venlafaxine levels in kidney tissue measured as a tissue/serum drug ratio, while a dose of 200 mg/kg of extract increases fluoxetine availability in liver, kidney and brain tissues [76]. Consequently, the extrapolation of the in vitro or rodent results to human situation is complicated and, in fact, contrasting evidence of interactions comes also from clinical studies using G. biloba. Treatment with G. biloba extract (240 mg/day for 2 weeks), in healthy volunteers, significantly decreased by 17% the AUC of alprazolam, CYP3A4 substrate, but did not affect the t½ [77]. Accordingly, similar results were shown in another study in healthy human volunteers treated with G. biloba extract (240 mg/day for 4 weeks) where a decrease in Cmax by 31% and in the AUC by 34% for midazolam, CYP3A4 substrate was observed [78]. Conversely, G. biloba extract (240 mg/day for 4 weeks) did not modify the serum 1-hydroxymidazolam midazolam ratio (used as an in vivo index of CYP3A-mediated drug metabolism) either in young [38] or in elderly [39] healthy subjects. However, successively, it has been shown that the use of a single post-dose midazolam concentration is of limited usefulness to predict CYP3A4-mediated drug interactions [79]. Further data were obtained by Uchida et al. [79] in male healthy volunteers where a significant decrease in the oral clearance (26%) and an increase in the AUC (25%) for midazolam were observed after treatment with G. biloba extract (EGb 761; 360 mg/day for 4 weeks) [80]. It can be presumed that the dose (360 vs. 240 mg) and the type of ginkgo extract utilized were responsible of the contrasting results observed with midazolam. Interestingly, concomitant oral administration of nifedipine (CYP3A substrate) and G. biloba extract did not modify the plasma concentration of the drug except in two of eight human subjects [81]. In these volunteers, G. biloba extract (240 mg) induced a doubled nifedipine Cmax and the appearance of long-lasting and intense side effects, such as dizziness, hot flashes and headaches [81], suggesting that ginkgo may act as an enzyme inhibitor during acute treatment. All these clinical results show that an interaction between G. biloba extract and CYP3A substrate drugs cannot be anticipated, but never excluded; however, it is difficult to conclude if an induction or inhibition of drug metabolizing enzymes or transporters occurs. Greenblatt and colleagues [81] observed that the co-administration of a single dose (360 mg) of G. biloba extract did not alter the pharmacokinetics of flurbiprofen, CYP2C9 substrate [82]; likewise, treatment for 7 days with G. biloba extract did not affect the pharmacokinetics of warfarin, another CYP2C9 substrate drug [83]. Conversely, tolbutamide AUC significantly decreased after treatment with EGbl 761 extract (360 mg/day) for 4 weeks [80]. Overall, these data would suggest that the duration of treatment may be responsible for the differences observed in healthy volunteers. Contrasting results were also obtained on the effects of ginkgo in healthy volunteers who were taking CYP2C19 substrate drugs. The induction of CYP2C19 activity observed by Hellum et al. [84] in human cultured hepatocytes could explain the effects observed by Yin et al. [83] in healthy Chinese subjects where the treatment for 12 days with G. biloba extract (280 mg/day) produced omeprazole hydroxylation in a CYP2C19 genotype-dependent manner [85]. Moreover, in either CYP2C19 extensive or poor metabolizer, G. biloba extract (240 mg/day for 12 days) did not induce effects on pharmacokinetics of voriconazol, a substrate of CYP2C19 [86]. Similar negative results were shown by Zuo and co-workers [85] on the CYP2C19-mediated N-demethylation of diazepam in healthy volunteers; based on the finding that 90% confidence intervals of the mean ratios of AUC(0-408) and Cmax of diazepam, both in the absence and presence of G. biloba extract, were within the no-effect boundary of 80–125% (equivalence range) [85]. The authors concluded that no clinical robust interaction occurs with the extract [87]. Of interest, the analysis of tabulated arithmetic means and standard deviations of AUC(0-408) and Cmax indicates that G. biloba extract supplementation leads to a statistically significant decrease by 37% and 25% of diazepam AUC and Cmax, respectively, and to a significant 17% increase in N-demethyldiazepam AUC(0-408) [87]. Of course, the statistical analysis performed by Zuo and co-workers [85] is appropriate as the confidence intervals convey a probability of the magnitude of the interaction [87]. However, the application of tests gives information on whether or not the systemic exposure differences are statistically significant (p < 0.05) but not whether they are clinically pertinent. Nevertheless, in the studies with medicinal plants, a number of factors, including the duration of treatment, the variability of the extract composition and the limited number of subjects recorded (Table 2), could influence any statistically significant changes in the pharmacokinetic parameters. In fact, it cannot be excluded that a reduction in the AUC by about 35% may significantly influence the therapeutic response of a drug; this may not be the case with diazepam as its metabolites remain active. In vitro results showing the induction of G. biloba on CYP2B6 [72], were validated by a clinical case that showed concomitant virologic failure with a marked decrease in the plasma concentrations of efavirenz, a CYP2B6 substrate drug, in an HIV-infected patient who also took G. biloba extract for some months [88]. The last remark would indicate that the intake of G. biloba decreases oral bioavailability and/or improves the systemic hepatic clearance of efavirenz, thus suggesting a serious precautionary note on ginkgo supplementation by patients who also take drugs substrate of CYP2B6. Moreover, no information on the dosage and the type of extract used by the patient described by Wiegman and colleagues [86] restricts the power of this observation and does not allow any generalization to be made [88]. Actually, treatment with G. biloba (120 mg twice daily for 14 days) in healthy volunteers did not significantly change the pharmacokinetics of bupropion, CYP2B6 substrate drug, although the extract significantly increased Cmax and reduced t½ of hydroxybupropion [89]. Reduced plasma levels of efavirenz reported by Wiegman et al. [86] may result from an induction of CYP3A4 also implicated in the drug metabolism [88]. Although G. biloba extract increased the expression of MDR transporter in vitro [71,72], treatment with the extract did not alter the pharmacokinetics of two substrate drugs for P-gp, digoxin [90] and fexofenadine [78]. Surprisingly, in healthy volunteers, the administration of G. biloba extract (360 mg/day for two weeks) significantly increases the Cmax and AUC of another substrate drug for P-gp, i.e., talinolol, but it does not affect its t½ [91], suggesting that G. biloba operates as an inhibitor of intestinal P-gp. Incidentally, by in vitro results [92], it can be supposed that flavonoids in the extract may have inhibited intestinal efflux transport of talinolol, thus effectively increasing its oral bioavailability. The involvement of P-gp transporter in G. biloba–drug interaction was successively observed by Blonk and colleagues [93] with raltegravir, a weak P-gp substrate [94]. In healthy volunteers, G. biloba extract (120 mg twice daily for 14 days) induced a geometric mean ratios (90% confidence intervals) difference (1.44 vs. 1.21) of Cmax and AUC(0–∞) when raltegravir was administered alone or with the extract trials [93]. Intriguingly, Zhou and colleagues [93] have demonstrated that the concentrations of ginkgolides necessary to inhibit or induce CYP isoforms in vitro were well above the concentrations obtained after intake of standard dose of the extract [95]. Incidentally, in human liver microsomes, hydrolysed form of GA, GB and GK tested on the activity of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 2E1 showed a value of IC50 of 10 µg/mL, too high to be reached in humans [95]. Indeed, in cryopreserved human hepatocytes, the mRNA expression and enzyme activities of CYP1A2, 2B6 and 3A4 were statistically increased only after incubation for 48 h with this high concentration (10 µg/mL) of the ginkgolides [95]. Consequently, in healthy volunteers, the administration of EGb 761® at standard dosage (120 mg twice daily or 240 mg once daily, for 8 days) did not affect the plasma concentration of caffeine, tolbutamide, omeprazole, dextromethorphan and midazolam used as a substrate of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A, respectively [96]. Similar results were achieved successively; in fact, no changes in the pharmacokinetics of cilostazol, CYP3A4 and CYP2C19 substrate drug, or its metabolites 3,4-dehydrocilostazol and 4′-trans-hydroxycilostazol, were observed after treatment with G. biloba extract (Ginexin®) (80 mg 120 mg twice daily for 7 days) in healthy volunteers [97]. However, a larger dose of G. biloba extract (360 mg for 14 days) in healthy volunteers weakly reduced AUC(0–∞) (10%) and Cmax (29%) and increased the distribution (volume of distribution (Vd) 31.95%) and elimina½ion (clearance (CL), 6.48%) of atorvastatin [98]. Atorvastatin is mainly transformed by CYP3A4 [99] but G. biloba extract treatment does not modify the atorvastatin metabolic pathway [98]. Different results were obtained by Dai and colleagues [98] (Chinese Clinical Trial Registry:ChiCTR-TTRCC-12002801), who observed an increase in the AUC(0–∞) (36%) and Cmax (32%) of simvastatin after treatment with G. biloba extract (120 mg twice daily for 14 days) [100]. Statins are taken up into hepatic cells mainly by OATP1B1 transporters and it is known that genetic polymorphism of this transporter is strongly associated with statins uptake; in particular, the 521CC genotype has been shown to elevate plasma concentrations of different statins [101,102]. It could be supposed that the decrease in the bioavailability of statins is associated with the capacity of G. biloba extract to also induce OATP1B1 activity if no effects have been observed on the cholesterol-lowering efficacy of these drugs [98,100]. Moreover, although, in the study of Guo and co-workers [96], subjects with the 521TT genotype are included, the data should be achieved on the activity or expression of intestinal and hepatic transporters after treatment with G. biloba in humans [98]. In conclusion, the in vitro results obtained by Zhou and colleagues [93] indicated that ginkgolides are active on metabolic enzymes only at a high concentration [95], not achievable after the administration of standard doses of G. biloba extract in a healthy subject, and these results can explain the lack of effect of the extract on pharmacokinetics of co-administered drugs (Table 2). However, more recent studies highlight the capacity of gingkolides to affect intestinal and/or hepatic transporters suggesting some precaution in G. biloba extract administration with their substrates.

Befund HOS-368828 · nifedipine · HOS-086289 · Originalquelle ↗

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Literatur & Herkunft

Pharmacokinetic Interactions between Herbal Medicines and Drugs: Their Mechanisms and Clinical Relevance ↗

© 2020 by the authors. Laura Rombolà; Damiana Scuteri; Straface Marilisa; Chizuko Watanabe; Luigi Antonio Morrone; Giacinto Bagetta; Maria Tiziana Corasaniti. Pharmacokinetic Interactions between Herbal Medicines and Drugs: Their Mechanisms and Clinical Relevance. DOI: 10.3390/life10070106 · CC BY 4.0

Quellen-Hash: 9e1aef561ce17db85d79e823c541e19427c32cc07e4f457a0cd0bd5efad9296c

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