http://www.paper.edu.cn Pharmacokinetic interactions of Journal of Psychopharmacology 18(2) (2004) 262–276 © 2004 British Association drugs with St John’s wort for Psychopharmacology ISSN 0269-8811 SAGE Publications Ltd, London, Thousand Oaks, CA and New Delhi 10.1177/0269881104042632 Shufeng Zhou Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore. Eli Chan Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore. Shen-Quan Pan Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore. Min Huang Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510089, PR China. Edmund Jon Deoon Lee Department of Pharmacology, Faculty of Medicine, National University of Singapore, Singapore. Abstract There is a worldwide increasing use of herbs which are often cancer patients receiving irinotecan treatment. St John’s wort did not administered in combination with therapeutic drugs, raising the alter the pharmacokinetics of tolbutamide, but increased the incidence potential for herb–drug interactions. St John’s wort (Hypericum of hypoglycaemia. Several cases have been reported that St John’s wort perforatum) is one of the most commonly used herbal antidepressants. A decreased cyclosporine blood concentration leading to organ rejection. literature search was performed using Medline (via Pubmed), Biological St John’s wort caused breakthrough bleeding and unplanned pregnancies Abstracts, Cochrane Library, AMED, PsycINFO and Embase (all from their when used concomitantly with oral contraceptives. It also caused inception to September 2003) to identify known drug interaction with serotonin syndrome when coadministered with selective serotonin- St John’s wort. The available data indicate that St John’s wort is a reuptake inhibitors (e.g. sertaline and paroxetine). Both pharmacokinetic potent inducer of CYP 3A4 and P-glycoprotein (PgP), although it may and pharmacodynamic components may play a role in these interactions. inhibit or induce other CYPs, depending on the dose, route and duration Because the potential interaction of St John’s wort with other drugs is a of administration. Data from human studies and case reports indicate major safety concern, additional systematic research on herb–drug that St John’s wort decreased the blood concentrations of amitriptyline, interactions and appropriate regulation in herbal safety and efficacy is cyclosporine, digoxin, fexofenadine, indinavir, methadone, midazolam, needed. nevirapine, phenprocoumon, simvastatin, tacrolimus, theophylline and warfarin, whereas it did not alter the pharmacokinetics of carbamazepine, dextromethorphan, mycophenolic acid and pravastatin. St John’s wort Keywords decreased the plasma concentration of the active metabolite SN-38 in cytochrome P450, drug interactions P-glycoprotein, St John’s wort Introduction (CYP)], and/or of drug transporters such as P-glycoprotein (PgP) (Walter-Sack and Klotz, 1996; Wilkinson, 1997; Evans, 2000; There is a worldwide increasing use of herbs which are often Ioannides, 2002; Zhou et al., 2003). The interplay of both intestinal administered in combination with therapeutic drugs, raising the PgP and CYP3A4 determines bioavailability of many drugs. Thus, potential for herb–drug interactions. Pharmacokinetic herb–drug the modulation of intestinal PgP and CYP3A represents an impor- interactions arise through altered absorption, metabolism, distribu- tant mechanism for the enhanced or reduced bioavailability of tion and/or excretion of drugs. Frequently, the underlying mecha- coadministered drugs. Furthermore, combined use of herb with nism of altered drug concentrations by concomitant herbal drug may mimic, increase, or reduce the effects of either interact- medicines is either induction or inhibition of hepatic and intestinal ing compound, resulting in clinically important herb–drug interac- drug-metabolizing enzymes [in particular, cytochrome P450s tions (Fugh-Berman, 1999, 2000; Fugh-Berman and Ernst, 2001; 中国科技论文在线 http://www.paper.edu.cn Figure 1 Chemical structures of the major constituents of St John’s wort Izzo and Ernst, 2001). Synergistic therapeutic effects may lead to Literature search unfavourable toxicities and complicate the dosing regimen of long- term medications, while antagonistic interactions will result in The literature was reviewed to identify all pertinent case reports, decreased efficacy and therapeutic failure. case series and animal and human studies. A literature search was St John’s wort (Hypericum perforatum) is one of the most performed using the following databases: Medline (via Pubmed), commonly used herbal medicines for the treatment of depression Biological Abstracts, PsycINFO, Cochrane Library, AMED (Allied (Di Carlo et al., 2001; Bilia et al., 2002; Schulz, 2002). St John’s and Complementary Medicine), Biosis Previews and Embase (all wort is a complex mixture of over two dozen constituents, includ- from their inception to September 2003). In addition, a number of ing flavonols, flavonol glycosides, biflavones, naphthodanthrones, Chinese journals related to herbal studies were searched manually acylphloroglucinols and phenylpropanes (Fig. 1) (Erdelmeier, from the first publication date onwards. The terms used included St 1998; Obach, 2000). Among these, hyperforin is the major John’s wort, hyperforin, hypericin, hypericum, herb, CYP, PgP and constituent responsible for its antidepressant activity because it drug interactions. All animal and human studies performed in vitro inhibits the reuptake of neurotransmitters (e.g. serotonin, noradren- and in vivo relating to the drug interactions with St John’s wort aline and dopamine) in synapses (Moore et al., 2000). Due to the were included. Human studies including case reports, case series, extensive use and concern of drug interactions, the effects of clinical trials or other types of studies, were all included. St John’s wort on the pharmacokinetics and pharmacodynamics of some clinically important drugs have been investigated in humans. In addition, spontaneous reports and published case reports pro- Effects of St John’s wort on CYPs and PgP vide supportive evidence for the interactions of St John’s wort with certain drugs. This review highlights the reported drug interactions Effects on CYPs with St John’s wort, with an emphasis on the possible underlying The CYP superfamily, containing 57 genes (Nelson, 2003), con- mechanisms and clinical outcomes. tributes to the metabolism of a variety of xenobiotics including 中国科技论文在线 http://www.paper.edu.cn therapeutic drugs, carcinogens, steroids and eicosanoids A drug interaction occurring in vivo is likely if [I]/Ki > 0.2, (Gonzalez, 1990; Nelson et al., 1996; Rendic and Di Carlo, 1997; where [I] is the maximum unbound plasma concentration (Ito et Nebert and Russell, 2002; Rendic, 2002). The relative abundance al., 1998). The maximum plasma concentration (Cmax) of hyper- of the hepatic CYPs in humans has been determined as: CYP1A2 forin is 0.17–0.50 µM in humans following a single dose (300 mg) (13%), 2A6 (4%), 2B6 (< 1%), 2C (20%), 2D6 (2%), 2E1 (7%) of standardized hypericum extracts containing 5% hyperforin and 3A4 (30%) (Shimada et al., 1994; Rendic and Di Carlo, 1997). (Biber et al., 1998; Agrosi et al., 2000). Thus, an [I]/Ki of 0.35– Consistently, the significance of the individual CYP enzyme in 1.04 for CYP3A4, 0.11–0.33 for CYP2C9 and 0.09–0.28 for human drug metabolism varies, with CYP3A, CYP2D and CYP2C CYP2D6 would be expected. This would raise the potential for being responsible for the metabolism of 50%, 25% and 20%, drug interactions with a number of substrates of these CYP respectively, of the currently known drugs (Bertz and Granneman, enzymes. These include amitriptyline and dextromethorphan 1997; Rendic and Di Carlo, 1997). All CYPs are subject to induc- (CYP2D6), warfarin, tolbutamide and phenprocoumon (CYP2C9), tion and inhibition by exposure to a wide variety of xenobiotics and HIV protease inhibitors, midazolam, oral contraceptives and including various herbs. Herb–drug interactions can frequently cyclosporine (CYP3A4). On the other hand, the Cmax of hypericin arise when drugs and herbs are coadministered, and the herb was 0.03–0.15 µM after the administration of 300 mg hypericum modulates the metabolic clearance of the drug by inhibition or extracts containing 0.3% hypericin (Staffeldt et al., 1993, 1994; induction of a specific CYP enzyme (Zhou et al., 2003). Chi and Franklin, 1999). Therefore, the [I]/Ki ratio will fall to Studies performed in vitro have demonstrated that St John’s 0.01–0.04 which is much lower than 0.2, suggesting that hypericin wort extract is a potent inducer of CYP2B6 and 3A4, and the alone appeared not to alter the metabolism of substrates of responsible constituent is hyperforin (Moore et al., 2000; CYP2D6, 2C9 and 3A4. It should be noted that the potential for Wentworth et al., 2000; Goodwin et al., 2001). Hyperforin, but not inhibition in vivo depends not only on the inhibitory potency (Ki), hypericum extracts, resulted in a marked induction of CYP3A4 but also on the overall disposition properties of the inhibitor (e.g. expression after treatment of primary human hepatocytes. Studies the extent of its intestinal absorption and plasma protein binding, performed in vitro have shown that hyperforin is a potent ligand uptake into the liver and clearance). More importantly, in the case (Ki =27nmol) for the pregnane