1.0 Gingko biloba
Ginkgo biloba is an herb extracted from the leaves of the tree. It has been traditionally used for improvement of blood flow (vasodilation), protection of cells from oxidative damage (antioxidation) and enhancement of memory and concentration. The herb is known to induce CYP450 enzymes such as CYP2C9, CYP2C19 and CYP2B, changing the metabolism of several drugs.2 Hence, concomitant intake of some drugs with Ginkgo may give rise to herb-drug interactions which can cause serious adverse effect.
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1.1 Antiepileptic drugs
A recent pharmacogenetic study with 18 volunteers revealed significant inductive effect of CYP2C19 by Ginkgo. Omeprazole which has CYP2C9 activity was used as a substrate. The results demonstrated that Ginkgo decreased the AUC of omeprazole by a significant amount. Besides, the plasma concentrations of omeprazole and its metabolite were reduced by almost 30% when compared to controls. From the results obtained, it might be deduced that Ginkgo reduces serum concentrations of antiepileptic drugs which are substrates of CYP2C19 like phenytoin, phenobarbital and diazepam.3
Ginkgo might also induce CYP2B activity. According to study by Kubota et al 2004, Ginkgo was shown to reduce the hypnotic potency of phenobarbital (50 mg/kg) in rats. The maximum plasma concentration and AUC of phenobarbital were reduced by 40% and 20%, respectively. These might be due to induction of CYP2B activity by Ginkgo since phenobarbital is a substrate for CYP2B in rats, leading to the possible herb-drug interaction.3
Study also shows that Ginkgo contains a potent neurotoxin, which is a vitamin B6 derivative. It is also known as Ginkgotoxin or 4-O-methopridoxine.2, 3 The neurotoxin is said to be responsible for the seizure activity. It is a competitive antagonist of pyridoxil phosphate which is a coenzyme of the glutamate decarboxylase. Inhibition of this coenzyme inhibits the GABA synthesis. This interaction might hence diminish the effect of antiepileptic drugs.
1.2 Anticoagulants medication
One of the concerns associated with Ginkgo is the increase risk of bleeding. Several cases have been reported when taking Ginkgo and anticoagulant drugs like aspirin and warfarin simultaneously. The proposed mechanism of bleeding caused by Ginkgo is via the action of ginkgolide B. According to Smith et al. 1996, Ginkgolide B is a component of Ginkgo which acts as a platelet-activating factor (PAF) antagonist. It is reported to displace PAF from its receptor- binding site, thus inhibiting PAF and results in reduced platelet aggregation and eventually bleeding. Nevertheless, some clinical studies have shown that Ginkgo does not decrease PAF-mediated platelet aggregation as well as prothrombin times.4
Warfarin is metabolised by CYP2C9 enzymes. An in vitro study by Gaudineau et al. 2004 stated that Ginkgo inhibits CYP450 enzymes, mainly CYP2C9. Hence, it is possible that this inhibition might lead to increase in warfarin levels and subsequently greater anticoagulant action. However, there are some contradicting studies which reported that Ginkgo induces rather than inhibits hepatic CYP, including (S)-warfarin hydroxylase. It is also reported that bilobalide found in terpene trilactone fraction of Ginkgo is responsible for the induction. This will thus reduce the efficacy of anticoagulants rather than enhancing the anticoagulant action.4
It remains unclear whether Ginkgolide B increase bleeding and whether Ginkgo potentiates or decreases the anticoagulant effect of warfarin in vivo. Nevertheless, it is recommended that for patients on warfarin or other anticoagulants therapy to not take ginkgo-containing products due to a possible risk of serious bleeding.
2.0 Hypericum Peforatum (St. John’s Wort)
St. John’s Wort preparations may interact with medicines either by increasing the rate of their metabolism or increasing levels of neurotransmitters.
2.1 Drugs metabolized by CYP-450
St. John’s Wort interferes with metabolism of drugs by inducing some CYP450 enzymes in the liver and gut. For instance, the main enzyme affected is CYP3A4, as well as 1A2 and 2C9. This results in decrease in blood levels and efficacy of some drug metabolised by CYP450 enzyme.
The principle behind the induction might be due to presence of hyperforin, which is a component of St. John’s Wort. A study by Moore et al. has shown that hyperforin activates a CYP3A4 regulator transcription. This activation thus induces CYP3A4 expression in human liver cells, thus increase the metabolic rate of drugs and subsequently decrease in therapeutic level. It can be deduced that St. John’s Wort inhibits CYP3A4 acutely and induces this enzyme upon repeated administration based on a systematic review.5
An example of this herb-drug interaction is St. John’s Wort and antiretroviral drugs such as protease inhibitors (PI) and nonnucleoside reverse transcriptase inhibitors (NNRTI). St. John’s Wort has been shown to decrease plasma concentrations of the drugs by CYP3A4 induction. The effects may also be due to induction of P-glycoprotein. For instance, there was a significant reduction in concentrations of indinavir when taken concurrently with St. John’s Wort in an open-label study.5 This will lead to loss of viral control or development of virus resistance.
2.2 Antidepressants medication
St. John’s Wort also increases the neurotransmitter levels in the brain particularly serotonin through additive effect on selective serotonin reuptake inhibitor (SSRI) antidepressants such as fluoxetine and paroxetine. These interactions may lead to mental state changes, sweating, increased blood pressure and motor effects due to increase in serotonin level.
Studies have demonstrated that St John’s Wort inhibits the synaptosomal uptake of certain neurotransmitters. It inhibits the uptake of 5-HT, noradrenaline, dopamine, glutamate and GABA. This action is not related to specific binding of the St. John’s Wort to the different transporter molecules, but associated with mechanisms related to Na+ conductive pathways.6
It is found that chronic administration of St. John’s Wort downregulates ?1-adrenoceptors and upregulates postsynaptic 5-HT1A receptors. Nevertheless, the study shows St. John Wort’s upregulates 5-HT2 receptors unlike other antidepressants.6
References
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Kupiec T, Raj V. Fatal Seizures Due to Potential Herb-Drug Interactions with Ginkgo Biloba. Journal of Analytical Toxicology 2005 Oct; 29:755-58
Landmark CJ, Patsalos PN. Interactions between antiepileptic drugs and herbal medicines. Bol. Latinoam. Caribe Plant. Med. Aromaticas 2008; 7(2):109-18
Takia Y, Yokotania K, Yamadab S, Shinozukac K, Kubotad Y, Watanabed Y, Umegakia K. Ginkgo biloba extract attenuates warfarin-mediated anticoagulation through induction of hepatic cytochrome P450 enzymes by bilobalide in mice. Phytomedicine 2012 Jan 15; 19(2):177-82
Hammerness P, Basch E, Ulbricht C, Barrette EP, Foppa I, Basch S, Bent S, Boon H, Ernst E. St. John’s Wort: A Systematic Review of Adverse Effects and Drug Interactions for the Consultation Psychiatrist. Psychosomatics 2003 July- Aug; 44(4):271-82
Carloa GD, Borrellia F, Izzoa AA, Ernst E. Is St John’s wort a ‘Prozac-like’ herbal antidepressant? Trends in Pharmacological Sciences 2001Nov 1; 22(11):559
