The Influence of St. John’s Wort on CYP2C19 Activity with Respect to Genotype

Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan 410078, China.
The Journal of Clinical Pharmacology (Impact Factor: 2.48). 06/2004; 44(6):577-581. DOI: 10.1177/0091270004265642
Source: PubMed


Induction of cytochrome P450 isozymes is the major cause for clinical drug interactions of St. John’swort. The relationships of St. John’swort to cytochrome P450 isoforms have been fully investigated, but its effect on CYP2C19 is lacking. Thus, the aim ofthe present study was to observe the effect of St. John’s wort on CYP2C19 activity using CYP1A2 as a control. Twelve healthy adult men—6 extensive metabolizers of CYP2C19 (2C19*1/2C19*1) and 6 poor metabolizers (42C19*2/2C19*2 and 22C19*2/2C19*3) —were enrolled in a twophase, randomized, crossover manner. All subjects took a 300-mg St. John’swort tablet or placebo three times daily for 14 days, and then the activities of CYP2C19 and CYP1A2 were measured using mephenytoin and caffeine. It was found that St. John’s wort treatment significantly increased CYP2C19 activity in CYP2C19 wild-genotype subjects, with urinary 4 -hydroxymephenytoin excretion raised by 151.5%±91.9% (p = 0.0156), whereas no significant alteration was observed for CYP2C19 poor metabolizers. Repeated St. John’s wort administration did not affect the CYP1A2 phenotypic ratio for both CYP2C19 genotype subjects. In conclusion, St. John’s wort is an inducer to the human CYP2C19, and clinicians should pay great attention when St. John’s wort is added to or withdrawn from an existing drug regimen containing substrates for such enzymes.

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Available from: GL Chen, Oct 08, 2015
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    • "Hypericum perforatum's ability to act as a substrate of both CYPs and P-gp has been widely confirmed in vitro (Perloff et al., 2001), in vivo (Imai et al., 2008), and in clinical studies (Xie et al., 2005). In the latter case, HP induces the activity of several CYP isozymes including CYP3A4, CYP2E1, and CYP2C19, thereby increasing the metabolism of many drugs (Gurley et al., 2005; Wang et al., 2004). Moreover, HP's effect upon CYP3A4 has been studied in greater detail where HP administration via the oral route affected midazolam metabolism to a greater extent than via the intravenous route, which suggests that HP primarily acts via intestinal, and not hepatic, CYP3A4 (Wang et al., 2001; Dresser et al., 2003). "
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    ABSTRACT: Hypericum perforatum (HP) belongs to the Hypericaceae family and is one of the oldest used and most extensively investigated medicinal herbs. The medicinal form comprises the leaves and flowering tops of which the primary ingredients of interest are naphthodianthrones, xanthones, flavonoids, phloroglucinols (e.g. hyperforin), and hypericin. Although several constituents elicit pharmacological effects that are consistent with HP's antidepressant activity, no single mechanism of action underlying these effects has thus far been found. Various clinical trials have shown that HP has a comparable antidepressant efficacy as some currently used antidepressant drugs in the treatment of mild/moderate depression. Interestingly, low-hyperforin-content preparations are effective in the treatment of depression. Moreover, HP is also used to treat certain forms of anxiety. However, HP can induce various cytochrome P450s isozymes and/or P-glycoprotein, of which many drugs are substrates and which are the main origin of HP-drug interactions. Here, we analyse the existing evidence describing the clinical consequence of HP-drug interactions. Although some of the reported interactions are based on findings from in vitro studies, the clinical importance of which remain to be demonstrated, others are based on case reports where causality can, in some cases, be determined to reveal clinically significant interactions that suggest caution, consideration, and disclosure of potential interactions prior to informed use of HP. Copyright © 2013 John Wiley & Sons, Ltd.
    Phytotherapy Research 05/2014; 28(5). DOI:10.1002/ptr.5050 · 2.66 Impact Factor
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    • "The inductions and inhibition of CYP enzymes by herbs in the presence of a prescribed drug has led to adverse effects. Herbal medicines such as St. John's wort (Hypericumperforatum ), ginseng (Ginseng sp.), gingko (Gingko biloba), and grapefruit juice show clinical interactions when co-administered with medicines (Ernst 2002; Saxena et al. 2008; Wang et al. 2004). In South Korea, many people use complementary and alternative medicine (CAM) to cope with illness or enhance overall health. "
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    ABSTRACT: Puerarin [4H-1-benzopyran-4-one,8-b-D-glucopyranosyl-7-hydroxy-3-(4-hydroxyphenyl)] is the major bioactive constituent in galgeun, which is the dried root of Puerariae Radix. For more than 2,000 years, galgeun has been widely used as an herbal medicine for its potential benefits on the treatment of common cold, diabetes and cardiovascular diseases in Northeastern Asia including Korea. To investigate whether puerarin participates in drug-herb interactions, this study examined the in vitro inhibitory effects of puerarin on the metabolic activities of cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), using specific Vivid®Substrates and recombinant CYP450 isozymes. The inhibitory effects of puerarin were observed in CYP2C19 and CYP2D6 with the % inhibitions of 37.9 (CYP2C19/miconazole) for 400 μg/mL and 27.6 (CYP2D6/quinidine) for 100 μg/mL, respectively. Slightly lower % inhibitions were seen in CYP1A2; 24.3 (CYP1A2/α-naphthoflavone) for 400 μg/mL. A significant dose–response effect was found in CYP2C19. (Pearson’s r = 0.999, P = 0.023). Little or no inhibitory activity was observed in CYP2C9 and CYP3A4. These findings imply that special attention should be paid to the use of puerarin when used concomitantly with drugs that are metabolized primarily by CYP2C19, CYP2D6, and CYP1A2. To identify the existence of potential interaction effects of puerarin on CYP2C19, CYP2D6, and CYP1A2, and to evaluate possible clinical significances of the effects, further in vivo or clinical studies should be explored.
    Oriental Pharmacy and Experimental Medicine 03/2013; 14(1). DOI:10.1007/s13596-013-0138-y
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    • "Carbamazepine St. John's Wort (Hypericum perforatum), is a commonly used herbal drug, and in one study, more than 5% of patients with epilepsy used the herbal drug for mood disturbance (mild to moderate depression) and fatigue (Patsalos et al., 2002). St. John's Wort has the potential to increase the metabolism of AEDs, since it induces CYP3A4, CYP2C9 and CYP2C19 and possibly by affecting drug transporter activity in the gastrointestinal tract (Roby et al., 2000; Wang et al., 2004; Zhou et al., 2004). St. John's Wort (300 mg tablet with 0.3% hypericin) did not, however, alter the plasma concentration of carbamazepine at steady state in an open cross over study of eight volunteers (5 men and 3 women aged 24-43 years old; Burstein et al., 2000). "
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    ABSTRACT: As a therapeutic class, antiepileptic drugs (AEDs) have a high propensity to interact and many interactions with concomitant medications have been described. Increasingly, herbal medicines are often used by patients with epilepsy and the risk that these may interact with their AED medication is now being realised. The purpose of this review is to highlight the interactions that have been reported between AEDs and herbal medicines. Overall, the published data are sparse and comprise of both pharmacodynamic (preclinical only) and pharmacokinetic (preclinical and clinical) interactions. Pharmacodynamic interactions between diazepam and the Chinese herb Saiboku-to and with Ginkgo biloba, and between phenytoin, valproate and gabapentin and Centella asiatica have been described. Pre-clinical studies suggest that the Japanese herbs Sho-seiryu-to and Sho-saiko-to, the herbal infusion preparation from Cassia auriculata, the traditional Chinese herbal medicine Paeoniae Radix and the herb Mentat can affect the pharmacokinetics of carbamazepine by various mechanisms. Pharmacokinetic interactions have also been reported with phenytoin (Paenoniae Radix, Ayurvedic syrup shankhapushpi), phenobarbital (Ginkgo biloba) and diazepam (the Chinese herbs Angelica dahurica and Salvia miltiorrhiza Bge). Clinical studies have reported a reduction in serum carbamazepine concentrations when co-administered with the traditional Chinese herb Free and Easy Wanderer Plus and also a reduction in serum midazolam concentrations by Echinacea and by St John¿s Wort. The mechanism of these interactions is considered to be induction of hepatic metabolism. In contrast, piperine elevates serum phenytoin concentrations, possibly be enhancing the gastrointestinal absorption of phenytoin. More research and information are required in order to clarify the propensity of AEDs and herbal medicine to interact and therefore potentially compromise the therapeutics of AEDs.
    Boletin Latinoamericano y del Caribe de Plantas Medicinales y Aromaticas 01/2008; 7(2). · 0.33 Impact Factor
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