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B. St. John’s Wort
Tomlinson et al.
St. John’s wort, derived from the flowering tips of Hypericum perforatum,
provides another example where a herbal drug that has gained considerable
popularity in Western countries proved to be capable of causing important
herb-drug interactions. It appeared to be a safe alternative antidepressant with
an efficacy similar to low-dose tricyclic antidepressants or selective serotonin
reuptake inhibitors (65–69) apart from the risk that it might interact with the
serotonin reuptake inhibitors to produce a mild serotonin syndrome
(26,56,70,71). However, in 1999 reports started to appear of interactions
between St. John’s wort and a variety of drugs and it was shown to reduce
the plasma concentrations of digoxin (72) and theophylline (73) and to result in
breakthrough bleeding during oral contraceptive use (74). Case reports then
emerged suggesting interactions with cyclosporin could reduce the immunosuppressive
effect resulting in rejection of transplanted organs including heart
(75,76), liver (77), and renal (78–80) transplants. It was also shown to decrease
plasma levels of the HIV protease inhibitors indinavir (81) and nevirapine (82),
as well as amitriptyline (83) and some HMG CoA reductase inhibitors (84).
Studies examining the mechanism of these interactions showed that
administration of St. John’s wort extract to rats for 14 days resulted in a 3.8fold
increase in expression of the intestinal drug efflux transporter P-glycoprotein,
the product of the multidrug resistance (MDR) gene 1, and in a 2.5fold
increase in hepatic CYP3A2expression (85). In healthy volunteers
administration of St. John’s wort extract for 14 days resulted in 1.4- and
1.5-fold increased expressions of duodenal P-glycoprotein/MDR1 and
CYP3A4, respectively, and in a 1.4-fold increase in the functional activity
of hepatic CYP3A4 assessed by 14C-erythromycin breath test (85). Likewise,
St. John’s wort given for 16 days produced a 4.2-fold increase in expression of
P-glycoprotein and enhanced the P-glycoprotein-mediated drug efflux function
in peripheral blood lymphocytes of healthy volunteers (86).
Another study using an in vivo probe drug cocktail approach showed
that short-term administration of St. John’s wort had no effect on CYP
activities whereas long-term (2weeks) administration decreased the bioavailability
of oral midazolam by >50% but when midazolam was given intravenously
there was only a 20% decrease, indicating relatively selective
induction of CYP3A activity in the intestinal wall (87). There was no change
in CYP1A2, CYP2C9, or CYP2D6 activities as a result of St. John’s wort
administration (87). However, in the LS180 intestinal cell model St. John’s
wort increased the expression of CYP1A2in a concentration- and timedependent
manner (88). Conversely, incubation of St. John’s wort in vitro
with a panel of recombinant human CYP isoforms showed inhibition of the
1A2, the 2C6, and especially the 2C19 isoforms (89).