Interactions

St. John's wort has been shown to have many interactions with other drugs. Although one study found that St. John's wort has no effect on the cytochrome P450 (CYP) enzyme system (62), most studies have shown it is a potent inducer of CYP3A4, and some studies have shown it induces CYP1A2 and CYP2C9 (3,63-67). Other studies have not supported the induction of CYP1A2 and CYP2C9 by St. John's wort (68). Induction of CYP3A4 is of the greatest concern because it is an important enzyme involved with the metabolism of many prescription medications. Induction of CYP3A4 can lower serum concentrations of drugs taken in combination with St. John's wort, thus reducing the efficacy of the drug. In vitro studies have shown an inhibition of CYP2D6, 2C9, 3A4, 1A2, and 2C19. Hyperforin was shown to be a potent noncompetitive inhibitor of CYP2D6 and a competitive inhibitor of CYP2C9 and 3A4 (3). Hypericum extracts and hyperforin have been shown to significantly induce activity of CYP3A4 in hepatocytes (69). Another study performed on human hepatocytes found that the hyperforin component in St. John's wort is responsible for the drug interactions caused by CYP450 induction, and the hypericin constituent doesn't seem to affect drug metabolism (70). Hyperforin has been shown to be a potent ligand for the pregnane X receptor, a nuclear receptor that regulates the expression of CYP3A4 and P-glycoprotein (Pgp) (68,69,71,72). This significantly induces the activity of both systems. However, both hypericin and hyperforin can inhibit Pgp with acute treatment. Pgp is found in many tissues and actively pumps various drugs and natural products out of cells (71). Acute use of St. John's wort can lead to increased initial serum concentrations of drugs that use this transport pump. Chronic use of St. John's wort has the opposite effect and induces Pgp (71,73). Subjects treated with St. John's wort for 16 days had a 4.2-fold increase in Pgp expression (73). Induction of Pgp is important because it decreases the bioavailability of drugs that use the transporter.

There are numerous case reports where patients on a calcineurin inhibitor, such as cyclosporine or tacrolimus, began taking St. John's wort and developed significant reductions in plasma concentrations of the drugs (74-81). Both cyclosporine and tacrolimus are metabolized by the CYP3A4 enzyme system, and cyclosporine is also a substrate of Pgp (74,81). There are reports of acute graft rejections caused by low cyclosporine or tacrolimus serum concentrations in heart, liver, and kidney transplant recipients who were taking St. John's wort (75,76).

There are also reports of complications associated with the combined use of oral contraceptives and St. John's wort owing to enzyme induction. The most frequent complication is breakthrough bleeding, although there are also reports of unwanted pregnancies (82,83).

Patients with AIDS who are taking protease inhibitors and nonnucleoside reverse transcriptase inhibitors are at risk of being subtherapeutically treated because these drugs are metabolized by CYP3A4. Studies have shown that combined use of St. John's wort and indinavir reduced the area under the curve (AUC) of indinavir by 57% (84). The same held true for nevirapine with an increased oral clearance of 35%, thus significantly lowering the exposure to the drug (85).

Patients taking voriconazole to treat a fungal infection may also be at risk of being subtherapeutically treated if they are concurrently taking St. John's wort. One study found that the administration of St. John's wort caused a brief, clinically insignificant increase in voriconazole blood levels followed by a significant long-term reduction in voriconazole concentrations. The AUC of voriconazole was reduced by 59% after 15 days of 900 mg St. John's wort extract taken daily. This was assumed to be caused by voriconazole being metabolized by CYP3A4 and 2C19 (86).

Imatinib mesylate, a drug recently approved for the treatment of chronic myeloid leukemia (CML), can also be affected by St. John's wort. Because imatinib is primarily metabolized by CYP3A4 and is also a Pgp substrate, the usage of St. John's wort in combination with imatinib has resulted in a significant reduction in exposure to the drug compared to imatinib alone. This is potentially significant because therapeutic outcomes for patients with CML have been shown to correlate with the dose and drug concentrations of imatinib (87).

Another enzyme system that St. John's wort has been found to affect is topoisomerase II (Topo II). Hypericin was found to be an inhibitor of cleavage complex stabilization by Topo II inhibitors, used in cancer chemotherapy. Hypericin seems to intercalate into or distort DNA structure, precluding Topo II binding and/or DNA cleavage. Because hypericin appears to antagonize Topo II-poisoning chemotherapy drugs, concomitant usage of these medications could inhibit the antitumor effects of these drugs (67).

There have also been several reports of delayed emergence from anesthesia; decreased international normalized ratios (INRs) in patients taking warfarin; and decreased drug levels of digoxin, buspirone, methadone, mephenytoin, chlorzoxazone, and some benzodiazepines with concomitant use of St. John's wort (88-91).

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