DIET/NUTRIENT INTERACTIONS WITH DRUG TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 667

and nutrients with drug transporters as well as the potential clinical consequences of
these interactions. In this review we focus on the interactions of diet and nutrients with
drug transporters arising from in vitro and in vivo studies, with specific emphasis on
several major efflux transporters (e.g., Pgp, MRP, and BCRP) and uptake transporter
(e.g., OATP).

22.2. DIET/NUTRIENT INTERACTIONS WITH DRUG TRANSPORTERS

22.2.1. Interactions of Diet and Dietary Supplements with Drug Transporters

Dietary supplements are products (other than tobacco) intended to supplement the
diet. Many top-selling herbal products, such as St. John's wort, garlic, green tea,
ginseng, and milk thistle, are classified as dietary supplements. 29 , 39 Since their mar-
keting does not require Food and Drug Administration (FDA) approval, the potential
interactions of these herbal products with conventional drugs, in general, have not
been carefully evaluated, raising a serious concern about the safety of using these
products. Recent in vitro and in vivo studies have shown that many dietary items
and supplements can modulate the activities of both efflux and uptake transporters
and alter the pharmacokinetics of various therapeutic agents, resulting in clinically
important drug interactions (Table 22.1).

St. John's Wort St. John's wort is widely used in the treatment of depression as
an over-the-counter herbal medicine. 40 As a complex mixture, St. John's wort con-
tains multiple constituents, such as hypericin, pseudohypericin, hyperforin, and the
flavonoids quercetin and its methylated form, isorhamnetin. 41 , 42 A large number of
clinically relevant St. John's wort-drug interactions have been reported, many of
which are drug transporter-mediated interactions.

Effects on Drug Transporters Several studies have shown that St. John's wort in-
duced Pgp both in vitro and in vivo. In LS-180 intestinal carcinoma cells, Pgp ex-
pression was induced significantly after 3 days of exposure to St. John's wort (a
fourfold increase at 300

M) in a
dose-dependent fashion. The induction of Pgp in LS-180 cells resulted in enhanced
efflux and decreased accumulation of rhodamine 123, a fluorescent molecule that
acts as a probe of Pgp. 43 In an in vivo induction study, 14 days of administration of
St. John's wort increased the Pgp level significantly: the intestinal Pgp 3.8-fold in
rats and the duodenal Pgp level 1.4-fold in humans. 31

g/mL) or hypericin (a sevenfold increase at 3

Similarly, chronic treatment

with St. John's wort (3 600 mg/day for 16 days) caused a 4.2-fold increase in

Pgp expression level in the peripheral blood lymphocytes from healthy volunteers,
resulting in reduced accumulation of rhodamine 123. 44 The underlying mechanism
of Pgp induction by St. John's wort is presumably due to the activation of pregnane X
receptor (PXR), a nuclear receptor that regulates Pgp expression. It has been shown
that hyperforin, a major constituent of St. John's wort, is a potent agonist for PXR
with a K i value of 27 nM. 45 , 46

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