Ginkgo biloba

Synonym(s) and related species Fossil tree, Kew tree, Maidenhair tree. Salisburia adiantifolia Sm., Salisburia biloba Hoffmanns.

Constituents

• Ginkgo leaves contain numerous

  • • flavonoids including the biflavone glycosides such as

      • • ginkgetin, isoginkgetin,

        • bilobetin, sciadopitysin, and also some quercetin and kaempferol derivatives.

• Terpene lactones are the other major component, and these include

  • • • • Ginkgolides A, B and C, and bilobalide,

• Ginkgo extracts may be standardised to contain between 22 and 27% flavonoids (flavone glycosides) and between 5 and 12% terpene lactones, both on the dried basis.

• The leaves contain only minor amounts of ginkgolic acids, and some pharmacopoeias specify a limit for these.

• The seeds contain ginkgotoxin (4-O-methylpyridoxine) and ginkgolic acids.

Use and indications

• The leaves of ginkgo are the part usually used.

• Ginkgo is often used to improve cognitive function in cases of dementia and memory loss, and it has been investigated for use in the treatment of Alzheimer’s disease.

• The ginkgolides are thought to possess antiplatelet and anti-inflammatory properties and it has been used for cerebrovascular and peripheral vascular disorders, tinnitus, asthma and to relieve the symptoms of altitude sickness.

Ginkgo + Aminoglycosides

• Ginkgo appears to accelerate the appearance of amikacin-induced ototoxicity and to increase its ototoxic effects in rats.

Mechanism of action

• Because the development of ototoxicity is cumulative, if ginkgo accelerates this process, there is potential for ototoxicity to develop at a lower cumulative dose.

• The available evidence is weak, but until more is known it may be prudent to carefully consider the risks and benefits of continuing ginkgo during treatment with drugs such as the aminoglycosides.

Ginkgo + Antiepileptics

Case reports describe seizures in three patients taking valproate, or valproate and phenytoin, when ginkgo was also taken.

Mechanism

• Unknown. Ginkgo seeds (nuts) contain the neurotoxin 4-Omethoxypyridoxine (ginkgotoxin), which indirectly inhibits the activity of glutamate decarboxylase, which in turn results in seizure induction by lowering the levels of γ-aminobutyric acid (GABA).

• A large quantity of ginkgo nuts (about 70 to 80) alone have been reported to be the cause of seizures in a healthy 36-year-old woman.

• However, leaf extracts would not generally be expected to contain sufficient levels of this neurotoxin to be a problem.

• Another possible mechanism is induction of the cytochrome P450 isoenzyme CYP2C19 by ginkgo.

• Phenytoin is a substrate of CYP2C19 and therefore, in theory, ginkgo may increase the metabolism of phenytoin and thereby reduce its levels. Ginkgo has been seen to induce CYP2C19 in clinical studies.

Ginkgo + Calcium-channel blockers; Diltiazem

• Ginkgo may inhibit the activity of the cytochrome P450 isoenzyme CYP3A4 or P-glycoprotein, both of which would raise diltiazem levels by inhibiting its metabolism or increasing its absorption, respectively.

• However, in clinical studies, ginkgo had no clinically relevant effect on the P-glycoprotein substrate digoxin, or on the conventional CYP3A4 probe substrate, midazolam,

Ginkgo + Calcium-channel blockers; Nicardipine

• Ginkgo may induce the cytochrome P450 subfamily CYP3A, which would increase the metabolism of nicardipine, a CYP3A4 substrate, and reduce its levels.

• Nifedipine, below have shown inhibition of CYP3A4 and increased levels.

• Moreover, note also that clinically relevant CYP3A4 inhibition has not been see with the conventional CYP3A4 probe substrate, midazolam,

Ginkgo + Calcium-channel blockers ; Nifedipine

• Ginkgo has no significant effect on the pharmacokinetics of intravenous nifedipine, suggesting that ginkgo reduces the first-pass metabolism of nifedipine.

• Ginkgo may therefore inhibit the cytochrome P450 isoenzyme CYP3A4, which would reduce the pre-systemic metabolism of nifedipine, a CYP3A4 substrate, and increase its levels.

Ginkgo + Haloperidol

• Animal studies suggest that ginkgo may increase extrapyramidal effects in response to haloperidol, but clinical studies do not appear to have reported this effect.

• Haloperidol is a dopamine D2-receptor antagonist. It is thought that ginkgo may interfere with dopamine neurotransmission by scavenging nitric oxide, which in turn reduces locomotor activity.

Ginkgo + Phenobarbital

Mechanism

• Ginkgo may induce the cytochrome P450 isoenzyme CYP2B subfamily, which would increase the metabolism of phenobarbital, a CYP2B6 substrate, and reduce its levels.

• However, the modest reduction in levels seen with high-dose ginkgo does not explain the marked reduction in sleeping time.

Ginkgo + Proton pump inhibitors

Ginkgo induces the metabolism of omeprazole. Most other proton pump inhibitors are likely to be similarly affected.

Mechanism

It was concluded that ginkgo increases the metabolism (hydroxylation) of omeprazole by inducing the cytochrome P450 isoenzyme CYP2C19.

References

1. Biber A. Pharmacokinetics of Ginkgo biloba extracts. Pharmacopsychiatry (2003) 36, S32–7.

2. 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, 1072–8.

3. Vn Moltke LL, Weemhoff JL, Bedir E, Khan IA, Harmatz JS, Goldman P, Greenblatt DJ. Inhibition of human cytochromes P450 by components of Ginkgo biloba. J Pharm Pharmacol (2004) 56, 1039–44.

4. Sugiyama T, Kubota Y, Shinozuka K, Yamada S, Yamada K, Umegaki K. Induction and recovery of hepatic drug metabolizing enzymes in rats treated with Ginkgo biloba extract. Food Chem Toxicol (2004) 42, 953–7.

5. Hellum BH, Hu Z, Nilsen OG. The induction of CYP1A2, CYP2D6 and CYP3A4 by six trade herbal products in cultured primary human hepatocytes. Basic Clin Pharmacol Toxicol (2007) 100, 23–30.

6. Etheridge AS, Black SR, Patel PR, So J, Mathews JM. An in vitro evaluation of cytochrome P450 inhibition and P-glycoprotein interaction with goldenseal, Ginkgo biloba, grape seed, milk thistle, and ginseng extracts and their constituents. Planta Med (2007) 73, 731–41.

7. Miman MC, Ozturan O, Iraz M, Erdem T, Olmez E. Amikacin ototoxicity enhanced by Ginkgo biloba extract (EGb 761). Hear Res (2002) 169, 121–9.

8. Kupiec T, Raj V. Fatal seizures due to potential herb-drug interactions with Ginkgo biloba. J Anal Toxicol (2005) 29, 755–8.

9. Granger AS. Ginkgo biloba precipitating epileptic seizures. Age Ageing (2001) 30, 523–5.

10. Miwa H, Iijima M, Tanaka S, Mizuno Y. Generalised convulsions after consuming a large amount of ginkgo nuts. Epilepsia (2001) 42, 280–1.

11. Ohnishi N, Kusuhara M, Yoshioka M, Kuroda K, Soga A, Nishikawa F, Koishi T, Nakagawa M, Hori S, Matsumoto T, Yamashita M, Ohta S, Takara K, Yokoyama T. Studies on interactions between functional foods or dietary supplements and medicines. I. Effects of Ginkgo biloba leaf extract on the pharmacokinetics of diltiazem in rats. Biol Pharm Bull (2003) 26, 1315–20.

12. Shinozuka K, Umegaki K, Kubota Y, Tanaka N, Mizuno H, Yamauchi J, Nakamura K, Kunitomo M. Feeding of Ginkgo biloba extract (GBE) enhances gene expression of hepatic cytochrome P-450 and attenuates the hypotensive effect of nicardipine in rats. Life Sci (2002) 70, 2783–92.

13. Kubota Y, Kobayashi K, Tanaka N, Nakamura K, Kunitomo M, Umegaki K, Shinozuka K. Interaction of Ginkgo biloba extract (GBE) with hypotensive agent, nicardipine, in rats. In Vivo (2003) 17, 409–12.

14. Smith M, Lin KM, Zheng YP. An open trial of nifedipine-herb interactions: nifedipine with St. John’s wort, ginseng or Ginko [sic] biloba. Clin Pharmacol Ther (2001) 69, P86.

15. Yoshioka M, Ohnishi N, Koishi T, Obata Y, Nakagawa M, Matsumoto T, Tagagi K, Takara K, Ohkuni T, Yokoyama T, Kuroda K. Studies on interactions between functional foods or dietary supplements and medicines. IV. Effects of Ginkgo biloba leaf extract on the pharmacokinetics and pharmacodynamics of nifedipine in healthy volunteers. Biol Pharm Bull (2004) 27, 2006–9.

16. Yoshioka M, Ohnishi N, Sone N, Egami S, Takara K, Yokoyama T, Kuroda K. Studies on interactions between functional foods or dietary supplements and medicines. III. Effects of Ginkgo biloba leaf extract on the pharmacokinetics of nifedipine in rats. Biol Pharm Bull (2004) 27, 2042–5.

17. Yin OQP, Tomlinson B, Waye MMY, Chow AHL, Chow MSS. Pharmacogenetics and herb-drug interactions: experience with Ginkgo biloba and omeprazole. Pharmacogenetics (2004) 14, 841–50.