لخّصلي

2.2.These interactions could also lead to the reduced efficacy of manyClinical studies have suggested that Hypericum perforatum could lower the steady-state plasma concentration of many drugs, including amitriptyline, cyclosporine, tacrolimus, digoxin, fexofenadine, methadone, midazolam, styrene coumarin, saquinavir, simvastatin, theophylline, and warfarin, causing severe herbalprescription drug interactions.In addition, the administration of St. John's wort to healthy volunteers over 14 days resulted in an 18% reduction in digoxin exposure after a single dose of digoxin, and a 1.4- and 1.5-fold increase in the expression of duodenal P-gp and CYP3A4, respectively Although St. John's wort induces both P-gp and CYP3A4, like rifampin, the reduction in the oral bioavailability of digoxin may be caused by the induction of intestinal P-gp due to a lack of significant metabolism by CYP3A4 [33].Its crude extract is a complex mixture of multiple active substances, including hypericin, quercetin, isoquercetin, biflavonoids, hyperforin, procyanidin, catechin, tannin, and chlorogenic acid.St. John's wort extracts containing hyperforin increase the expression of CYP-enzymes and P-gp mainly in the gut and liver which leads to a clinically relevant decrease of the bioavailability of CYP and P-gp substrates.Also, minor changes in drug bioavailability observed in clinical studies for valerian, echinacea, ginkgo and hawthorne are clinically not relevant, although in vitro studies point to drug interactions in vivo.Most anticancer drugs undergo Phase I and/or II metabolism and are substrates of Pglycoprotein, breast cancer resistance protein, multidrug resistance (MDR) associated proteins, and/or other transporters.For example, a clinical study in cancer patients reported that treatment of St John's wort at 900 mg/day orally for 18 days decreased the plasma levels of the active metabolite of irinotecan, SN-38, by 42%.Coadministration of St. John's wort and the HIV protease inhibitor indinavir reduced the latter's exposure by 57% in healthy volunteers [35].Herb-drug Interactions in Drug Metabolism and Pharmacokinetics 2.2.1.

2.2. Herb-drug Interactions in Drug Metabolism and Pharmacokinetics 2.2.1. Hypericum Perforatum Hypericum perforatum L. is currently the most widely used herbal medicine outside of China. It is mainly used to relieve conditions such as depression, anxiety, and skin inflammation. Its crude extract is a complex mixture of multiple active substances, including hypericin, quercetin, isoquercetin, biflavonoids, hyperforin, procyanidin, catechin, tannin, and chlorogenic acid. Among these, hypericin is the major antidepressant component; it inhibits the reuptake of neurotransmitters, including 5-hydroxytryptamine, norepinephrine, and dopamine. In vivo and in vitro studies in both animals and human have shown that Hypericum perforatum extract is a strong inducer of CYP3A4 [32,33]. St. John’s wort is one of the most commonly used over-the-counter herbal medicines in the United States and is widely used in the treatment of mild depression. However, the U.S. Food and Drug Administration (FDA) alerted health professionals to the risk of drug interactions with St. John’s wort [34]. The induction of intestinal P-gp by St. John’s wort is assumed to play a role in these phenomena. In addition, the administration of St. John’s wort to healthy volunteers over 14 days resulted in an 18% reduction in digoxin exposure after a single dose of digoxin, and a 1.4- and 1.5-fold increase in the expression of duodenal P-gp and CYP3A4, respectively Although St. John’s wort induces both P-gp and CYP3A4, like rifampin, the reduction in the oral bioavailability of digoxin may be caused by the induction of intestinal P-gp due to a lack of significant metabolism by CYP3A4 [33]. Coadministration of St. John’s wort and the HIV protease inhibitor indinavir reduced the latter’s exposure by 57% in healthy volunteers [35]. Pharmacokinetic herbdrug interactions are caused by an induction or inhibition of CYP450s or transporters (P-gp). St. John's wort extracts containing hyperforin increase the expression of CYP-enzymes and P-gp mainly in the gut and liver which leads to a clinically relevant decrease of the bioavailability of CYP and P-gp substrates. Contrarily, the bioactivation of losartan is reduced by milk thistle extracts which is due to an inhibition of CYP2C9. However, the 15 % reduction of the bioavailability of the active metabolite E-3174 is clinically not relevant. Also, minor changes in drug bioavailability observed in clinical studies for valerian, echinacea, ginkgo and hawthorne are clinically not relevant, although in vitro studies point to drug interactions in vivo. Since for herbal extracts a positive in vitro-in vivo correlation regarding the impact on drug bioavailability is rare, results from in vitro studies should be carefully interpreted [36]. Clinical studies have suggested that Hypericum perforatum could lower the steady-state plasma concentration of many drugs, including amitriptyline, cyclosporine, tacrolimus, digoxin, fexofenadine, methadone, midazolam, styrene coumarin, saquinavir, simvastatin, theophylline, and warfarin, causing severe herbalprescription drug interactions. There are increased reports on the interaction of herbal medicines and anticancer drugs that is becoming a safety concern. For example, a clinical study in cancer patients reported that treatment of St John's wort at 900 mg/day orally for 18 days decreased the plasma levels of the active metabolite of irinotecan, SN-38, by 42%. In healthy subjects, two weeks of treatment with St John's wort at 900 mg/day significantly decreased the systemic exposure of imatinib by 32%. In women with advanced breast cancer, co-administration of garlic supplement reduced the clearance of docetaxol by 23.1-35.1%, although the difference did not achieve statistical significance. Most anticancer drugs undergo Phase I and/or II metabolism and are substrates of Pglycoprotein, breast cancer resistance protein, multidrug resistance (MDR) associated proteins, and/or other transporters. Induction and inhibition of these enzymes and transporters is considered an important mechanism for herb-anticancer drug interactions [37]. These interactions could also lead to the reduced efficacy of many