Effect Of Ginkgo Biloba Extract And St John's Wort On The Pharmacokinetics Of Voriconazole And Bupropion In Vivo And The Impact On Herb-drug Interactions

Botanically derived therapies have been used for a variety of ailments for thousands of years. The belief that natural products are much safer than synthetic drugs and the use of herbal medicines has become increasingly popular throughout the world. Like synthetic drugs, herbal preparations also have potential to cause drug interactions. Some of these drugs can inhibit or induce liver cytochrome P450 activity. Thereby influence drug metabolism and maybe cause drug adverse action and drug interactions. Thus, for public safety there is a need to carefully study herb-drug interactions, especially for commonly used herbal products.Ginkgo biloba extract (GBE) is a popular herbal medicine and has received great attention in clinical therapy. Ginkgo biloba extract has some pharmacological functions, such as antioxidant, scavenging free radicals, anti-platelet-activating factor, the regulation of vascular activity, increased blood flow, neuroprotection. Interactions between GBE and other drugs are of increasing concern. Among these interaction,induction and inhibition of hepatic drug metabolizing enzymes by GBE have been investigated. Ginkgo biloba was shown to induce omeprazole hydroxylation in a CYP2C19 genotype-dependent manner in healthy male subjects. Therefore, Coadministration of Ginkgo biloba with omeprazole or other CYP2C19 substrates, like voriconazole, may reduce plasma voriconazole to subtherapeutic concentrations and in total loss of therapeutic effect.Voriconazole (VRC) is a new triazole broad spectrum second generation antifungal drug approved for systemic treatment of severe fungal infections. Voriconazole undergoes an extensive oxidative metabolism involving cytochrome P450 (CYP) enzyme isoforms CYP2C19, CYP3A4, and to a lesser extent, CYP2C9. CYP2C19 is characterised by a genetic polymorphism. According to their ability to express CYP2C19 and consequently according to the actual isoenzyme activity, individuals can be characterised as extensive metabolisers (homozygous and heterozygous EMs) and poor metabolisers (PMs).Studies have reported that ginkgo biloba administration to rats markedly increased the CYP content and CYP2B mRNA in the liver and intake of ginkgo biloba also induced various hepatic CYP enzymes, especially CYP2B-type enzymes.St John's wort (SJW) extracts have become popular natural medicines for the treatment of mild-to-moderate depression. Total sales of St John's wort in Europe were approximately $6 billion (US) in 1998. Because it is a conventional herbal drug available over the counter, it is often regarded as safe by the public. However, since 1998, one after another clinically relevant SJW-drug interactions, including numerous case reports and clinical studies, have been reported, such as the immunosuppressants cyclosporine and tacrolimus, the anticancer drug imatinib, the antihypertensive agent verapamil and talinolol, the antidepressant amitriptyline, the antifungal agent voriconazole, et al.Induction of cytochrome P450 isozynres is the major cause for clinical drug interactions of St John's wort. Pergnane x receptor, belonging to nuclear receptor superfamily, is mainly expressed in intestine and liver. SJW, in particular its active component hyperforin, activates PXR, thereby inducing CYP2B6 expression.Bupropion, an antidepressant and smoking cessation drug, is metabolized to its active metabolite hydroxybupropion almost exclusively by CYP2B6.As bupropion is a substrate for CYP2B6, it has the potential to interact with co-administered drugs that are inducers of this enzyme.Based on above information, our study was aimed to examine the possible effects of Ginkgo biloba extract as an inducer of CYP2C19 on single-dose pharmacokinetics of voriconazole in Chinese volunteers genotyped as either CYP2C19 extensive or poor metabolizers. To assess the effects of the two popular herbal products Ginkgo biloba extract and St John's wort on the pharmacokinetics of bupropion in healthy volunteers. In order to provide useful information for the clinical use of voriconazole and bupropion.The present series of studies have found that:1. This is the study investigating the potential effect of Ginkgo biloba administration on the metabolism of voriconazole. Our results show that administration of Ginkgo biloba 120 mg twice daily for 12 days to CYP2C19 extensive metabolizers and poor metabolizers had no statistically significant effect on the pharmacokinetics of single-dose voriconazole, as measured by AUC, which suggests that Ginkgo biloba does not significantly affect the metabolism of voriconazole following a single oral dose in healthy Chinese males. A wide interindividual variability between different CYP2C19 genotypes was also seen in the control phase in the AUC_0-∞ of voriconazole after administration of a single oral dose.2. The present study was undertaken to investigate the effects of oral administration of ginkgo biloba extract on the pharmacokinetics of bupropion in healthy volunteers. Our results show administration of ginkgo biloba(120mg, bid) for 14 days had no statistically significant effect on the pharmacokinetics of bupropion or its active metabolite hydroxybupropion, as measured by AUC, which suggests ginkgo biloba does not significantly affect the metabolism of bupropion following a single oral dose in healthy Chinese males.3. In this study, we evaluated the effect of St John's wort on oral bupropion pharmacokinetics in healthy volunteers before and after long-term consumption of St John's wort (325mg 3 times a day for 14 days).The major finding was that 14-days' treatment with St John's wort causes a significant increase in bupropion clearance and a significant decrease in bupropion AUC (P<0.05).Through in-depth study of herbal drugs on the impact of drug metabolism, basic theories of herbal drugs is conductive to the deepening and development, and also provided useful information for the clinical use of voriconazole and bupropion.