Cyclosporine
Two cases of heart transplant rejection in patients who took St. John's wort
while being treated with cyclosporin have been reported (Ruschitzka et al.
2000). One patient had been maintained uneventfully on a regimen of cyclosporin
(125 mg bid), azathioprine, and corticosteroids for 11 months. The other patient
had also been stable on an immunosuppressive regimen that included cyclosporin
(125 mg bid). Although cyclosporin levels had been within the therapeutic range
for both patients, ingestion of St. John's wort (300 mg tid) for three weeks
diminished blood concentrations of cyclosporin to subtherapeutic levels and
prompted episodes of rejection in each of these patients. Cyclosporin
concentrations returned to therapeutic range with discontinuation of St. John's
wort in both of these cases.
Additional reports of 30 interactions between cyclosporin A and St. John's
wort in kidney transplant recipients were recently described (Breidenbach et al.
2000). After beginning St. John's wort therapy, cyclosporin blood levels fell by
an average of 47%; cyclosporin dosages were increased 46% to account for this
drop. Upon discontinuation of St. John's wort, cyclosporin blood levels
increased by an average of 187%. While the mechanism for this interaction is not
entirely clear, St. John's wort may either decrease cyclosporin absorption,
induce cytochrome P-450 in the liver and/or small intestine, or induce
P-glycoprotein (a drug transporter) in the small intestine. Because cyclosporin
has a narrow therapeutic range, the researchers caution against concomitant use
of St. John's
wort.
Digoxin
The interaction between the hypericum extract of St. John's wort (900 mg/day)
and digoxin (0.25 mg/day) was investigated in a single-blind, placebo-controlled
parallel study in 25 healthy volunteers (Johne et al. 1999). The combination
resulted in decreased plasma concentrations of digoxin over the 10-day period.
This interaction was thought to involve induction of transport proteins,
specifically P-glycoprotein.
Loperamide
There is a report in the literature of a possible interaction between
loperamide and St. John's wort (Khawaja et al. 1999). A 39-year-old woman was
admitted to the hospital in a state of delirium. She had been taking St. John's
wort and valerian for 6 months, and she had recently ingested loperamide for
diarrhea. Because the patient's clinical condition resembled a MAOI reaction,
this interaction was thought to occur as a result of a MAOI-induced mechanism,
possibly associated with an interaction either between the herbal agents or the
herbal agents and
loperamide.
Monoamine
Oxidase Inhibitors (MAOIs)
Research regarding interactions between St. John's wort and MAOIs remains
incomplete and controversial. A recent report suggested that St. John's wort and
phenelzine, a MAOI, should not be used concomitantly (Miller 1998).
Oral
Contraceptives
Eight women between the ages of 23 and 31 who had used St. John's wort while
taking oral contraceptives reported breakthrough bleeding or changes in
menstrual bleeding (Yue et al. 2000). There have been additional reports cited
in the literature of breakthrough bleeding in women taking oral contraceptives
with St. John's wort (Ernst 1999). Because oral contraceptives are metabolized
via the cytochrome P450 pathway, enzyme induction is thought to be the mechanism
behind this
interaction.
Protease
Inhibitors
The Food and Drug Administration (FDA) has issued a public health advisory
concerning an interaction between indinavir and St. John's wort that resulted in
significantly decreased plasma concentrations of this protease inhibitor (FDA
2000). This advisory warning was based on results of an NIH-conducted open-label
study of eight healthy volunteers receiving indinavir (800 mg) and later
indinavir with St. John's wort (300 mg tid standardized to 0.3% hypericin) for
14 days (Piscitelli et al. 2000). Plasma concentrations of indinavir dropped
significantly from levels obtained prior to the introduction of St. John's wort.
This interaction may be secondary to induction of the cytochrome P450 metabolic
pathway.
The FDA recommends against concomitant administration of St. John's wort with
antiretroviral medications that are protease inhibitors or nonnucleoside reverse
transcriptase inhibitors because this interaction could lead to subtherapeutic
plasma concentrations of these medications with the potential for lack of
efficacy and/or resistance (FDA
2000).
Reserpine
St. John's wort antagonized the effect of the sympatholytic agent reserpine
in animal studies (Okpanyi and Weischer
1987).
Selective
Serotonin Reuptake Inhibitors (SSRIs)
In five cases, elderly patients receiving St. John's wort and prescription
antidepressants (SSRIs) developed symptoms of serotonergic syndrome, including
headache, dizziness, nausea, agitation, and anxiety (Lantz et al. 1999). A
washout period of two weeks has been recommended when switching between SSRIs
and St. John's wort because the combination of St. John's wort (600 mg) and
paroxetine (20 mg) reportedly resulted in symptoms of incoherence and lethargy
in a patient (Gordon 1998). Concomitant use of SSRIs with St. John's wort is not
recommended. If these agents are used concomitantly, patients should be
monitored very closely. Patients must be carefully weaned from one before
starting on the
other.
Theophylline
Use of St. John's wort supplement (300 mg bid standardized to 0.3% hypericin)
decreased a patient's theophylline concentration, requiring an increase in
dosage to 800 mg bid (Nebel et al. 1999). Discontinuation of St. John's wort
caused the theophylline concentration to more than double in this individual
case. St. John's wort may enhance hepatic enzyme (CYP1A2) activity, leading to
increased theophylline
clearance.
Tricyclic
Antidepressants (TCAs)
Unpublished data suggest that St. John's wort may lower plasma concentrations
of amitriptyline (De Smet and Touw 2000). This lends support to the possibility
that the mechanism of drug interactions with St. John's wort involves induction
of hepatic enzymes that are part of the cytochrome P450
system.
Warfarin
There have been seven case reports filed with the Medical Products Agency
(MPA) in Sweden involving reduced effectiveness of warfarin when taken
concomitantly with St. John's wort as evidenced by clinically significant
decreases in INR values (Yue et al. 2000). Adjustments in warfarin doses or
discontinuation of St. John's wort resulted in a return of INR values to desired
levels. This interaction may be due to induction of hepatic enzymes,
specifically cytochrome P450 2C9. In addition, there was a literature report of
lower serum concentrations of warfarin in a 75-year-old woman who also took St.
John's wort (Ernst 1999).