Dietary Supplement Practicum (12 of 21): Interactions between Supplements & Drugs

Dietary Supplement Practicum (12 of 21): Interactions between Supplements & Drugs


>>Cindy Davis: So, our last
speaker of the morning will be Dr. Bill Gurley who is a professor of
pharmaceutical sciences at the University
of Arkansas for Medical Sciences
College of Pharmacy. He is director
of the UAMS clinical
pharmacokinetics research laboratory and chair of the UAMS Institutional
Animal Care and Use Committee and
vice chair of the UAMS Department of
Pharmaceutical Sciences. His research interests
include mechanisms of herb/drug
interactions, toxicity of multiple component herbal dietary
supplements, phytochemical modulation
of human drug metabolizing enzymes and
drug transport proteins, pharmacokinetics
of phytochemicals in humans,
and botanical supplement use in
special populations. His presentation today
will be on interactions between supplements
and drugs. Please join me in
welcoming Dr. Gurley.>>Bill Gurley:
Right. So I want to thank — I want to thank
the Office of Dietary Supplements for inviting me
to speak again. I’ve been here
countless times and I certainly enjoy it and hopefully
they won’t run me off after this particular
presentation. But nevertheless, plants have certainly
been a source of drugs since time immemorial. But the issue of
drug interactions really didn’t come
to the forefront till after the
Second World War when drugs moved
from multi-component plant-based preparations to purified single ingredient
synthetic compounds. Now if you delve into
the medical literature like I often do,
it’s obvious that phytochemicals
have been recognized for their ability to modulate human
drug metabolism for many decades. And I think one
of the most — interactions most
often described is the ability for
cruciferous vegetables to modulate certain drug
metabolizing enzymes that can prevent
the activity of certain environmental
carcinogens. I think a group
you’re quite familiar with are
the isothiocyanates. But the concern for
herb/drug interactions really didn’t come to — didn’t come to the
forefront until 1991. And it was that year
that grapefruit juice was found to increase the oral
absorption of many drugs and possibly
their toxicity by inhibiting one of
the most important drug metabolizing enzymes
in the intestine and that’s one called
cytochrome P450 3A4. And just a quick survey. You guys familiar with
the whole grapefruit juice issue? Okay. Very good. I just want
to make sure that — all right. And so — but soon after the
grapefruit juice issue came into light
the Dietary Supplement Health and Education Act
was passed. And then a plethora
of unique phytochemicals became available
for consumption in the United States in the form of botanical
dietary supplements. Now the issue of herbal
dietary supplement drug interactions
really kind of started coming to
the forefront in 1998. And it was that year
that an article appeared in the Journal of the American
Medical Association. And the article was about
alternative medicine use in
the United States. In the article
the authors estimated that in 1997
15 million adults took prescription
medications concurrently with herbal remedies
or high-dose vitamins. Which is
a substantial percentage around 18 percent. Now in the article
the authors also went on to estimate that nearly
three million adults aged 65 years or older were also taking
conventional medications with
dietary supplements. And because the elderly
are our greatest consumers of
conventional medications then they may be
at an increased risk for herb/drug
interactions. Now you probably have
already heard quite a few surveys about dietary supplement
use in this practicum and certainly may hear
some more tomorrow. Roughly about
half of all the — of all the citizens
of the United States use some type of
dietary supplement. Most of the times
those are vitamins and minerals. But nevertheless
a number of — a number of other
surveys indicate that between 30 and 60
percent of all hospital patients use
botanical supplements on a regular basis. And I think
as a pharmacist one of the most important
surveys to me is the fact
that almost 20 to 30 percent of all
prescription drug users also take botanical
dietary supplements on a regular basis. And as
healthcare professionals I think it’s one
of the most important statistics to take away is the fact
that still — and I’ve been following
this statistic for quite some time and it kind of stays
around 40 percent. Around 40 percent
of all patients never reveal the fact that they’re taking
botanical dietary supplements to a healthcare
professional. So that can oftentimes
be quite problematic. Now there are whole
hosts of reasons — or whole host of reasons that may contribute to
herb/drug interactions. And I think, you know, a fairly obvious one
is that the more botanicals
you’re exposed to, and if you’re taking
conventional medications, the greater
the likelihood that there may be
an interaction. And of course
a lot of — not only we’re talking about single ingredient
dietary supplements but also multiple ingredient dietary
supplements can certainly increase
the likelihood. And of course you also
have to realize that herbal dietary
supplements are oftentimes
formulated with concentrated plant
extracts. All right? So they pick the plant
material, grind it up, and oftentimes extract either
hot aqueous solutions or sometimes
organic solvents, and concentrate
a lot of these — a lot of these unique
phytochemicals, then dry that off
and formulate it as a — as a powder or tablet
or capsule or whatever. So you’re getting —
you’re being exposed to much higher
concentrations of some of these
unique phytochemicals than you would if you
just consumed the plant in its natural state. And of course a lot
of the phytochemicals that we oftentimes
run across we know very little about their pharmacological
activity. All right? And so a nice example in
terms of just complexity is just Panax ginseng. There have been over 500
unique phytochemicals found in Panax ginseng
and several of — in fact I would say
the vast majority of those we know
very little about their pharmacological
activity. Now to kind of — to kind of hammer that
point a little more, this is just a partial
listing of some of the known phytochemical
constituents in St. John’s
wort extract. And of course you can
see there’s flavonoids and essential oils. And of course
the flavonoids are ubiquitous throughout
the plant kingdom. But a lot of species
will have their own
unique phytochemicals that may not be found
in any other species. And St. John’s wort is
a great example of that. And there are a few — a few categories like
the naphthodianthrones we see there on the left-hand
side of the screen. But at the bottom you’ll
notice I’ve got one highlighted in orange
instead of yellow. And that’s a compound
called hyperforin. And we’re going to talk
about hyperforin a little bit later. All right? But it’s
a very unique compound that makes St. John’s
wort very problematic with regard to herb/drug
interactions. Now. All right. So how do you initially
recognize whether or not a botanical
or dietary supplement’s going to pose a risk
for a drug — an herb/drug
interaction? Well, oftentimes
our first indicator comes from case reports that appear in
the medical literature. Now a single case report really can’t
establish causation. In fact — in fact,
a lot of epidemiologists would argue
that no case reports can
establish causation. However, if you start
to see numerous case reports reporting
the same thing there’s probably
some merit to that. All right? But nevertheless case
reports oftentimes can kind of help
you establish a hypothesis
to test in the future. And this also holds true
for the adverse event reports that are
submitted to the FDA through their
MedWatch program. And of course if you — if you do research
in this area or — and follow
the literature, there’s a tremendous
number of papers that are publishing
in vitro results. And Dr. Kurzer
talked about some in vitro issues earlier. And then it’s —
of course if you expose a cell line that expresses a drug
metabolizing enzyme or a transporter
or if you use — or if you utilize
purified enzymes and such, if you expose them
to a high enough concentration of a phytochemical
or to an extract, you’re going to see
an effect of some sort. All right?
Now the question is, is that
clinically relevant? And the problem is with
most in vitro studies is that they don’t
translate very well. In fact I would say the
vast majority of them don’t translate to the
in vivo condition. So to me the most
definitive means for assessing clinically relevant
herb/drug interactions is to actually
do prospective clinical studies
in humans. Now I know those
can be very expensive but nevertheless
they can be quite definitive
in their studies. And so what I’m going
to share with you are several studies
that we’ve done over the years to illustrate some
of these principles. All right. Now there are
two major categories of herb/drug
interactions. The first general
category is called a pharmacodynamic
interaction. And that’s just
a situation where the botanical has a
pharmacological property either very similar to a conventional
medication, therefore it may
exacerbate the conventional
medication’s effect, or it has an effect
just the opposite of a conventional
medication and therefore may
negate its effect. So let me just give you
two examples of some pharmacodynamic
herb/drug interactions that are well
recognized. And the first one
involves the ephedra-free
dietary supplements. Now you guys
may remember — some of you — some of you
may be too young to remember
the ephedra wars as I like to call them,
but back in the early — when DSHEA first
came out from 1994 until 2004 ephedra
containing dietary supplements
were on the market. And ephedra
is a plant source of a group of drugs
like ephedrine, pseudoephedrine, and
phenylpropanolamine, and a few others. And the ephedra
containing dietary supplements also contain natural
sources of caffeine. And it just so happens
that caffeine and ephedrine is a — is a pretty potent
combination. Well, the problem
with ephedra dietary supplements is there were a lot of
serious adverse events linked to their use,
issues of heart attacks, strokes, seizures,
psychosis, even some deaths. Some deaths of some
college athletes and some professional
athletes. And of course then you
had this media frenzy going on and pretty soon
sales of ephedra containing dietary supplements
started to plummet. Well of course
the dietary supplement manufacturers
are not fools. They just said okay, we’ll just take
the ephedra out and leave
everything else in, maybe add a few
other things. And so the
ephedra-free products started to catch up with
and soon surpass their ephedra
containing predecessors with regards to sales. All righty.
Now, so the question is are these
ephedra-free products any safer? And so the typical
components that you find in ephedra
-free supplements, they are primarily
natural sources of caffeine, although you will find some other
natural sources of other
sympathomimetic agents like synephrine
and phenylethylamines and yohimbine and such. But nevertheless the
typical caffeine sources include guarana,
green tea, kola nut, yerba mate,
and several others, and oftentimes
combinations of those and even throw in some synthetic
caffeine to boot. And it’s not uncommon for a lot of these
products to have pretty substantial
amounts of caffeine, as much as three
to six cups of coffee. And because —
so the question is are these high dose
caffeine containing products
any safer? All righty.
So now as I mentioned, the FDA took the ephedra containing
dietary supplements off the market in 2004.
All right. But soon after that you
started to see eerily similar case reports appearing in
the medical literature with these ephedra-free
dietary supplements. So here again issues
of heart attacks, stroke, seizures, exertional heat
illness, and such. So now the question
is well, you know, maybe ephedra wasn’t the entire problem.
All right. So I want to share
with you one of the few studies that have actually
been conducting with — conducted with ephedra-free
dietary supplements. And so we looked
at three very popular ephedra
-free supplements. One was called
Xenadrine EFX. Excuse me. Metabolift.
And then Zantrex 3. And you can see there on
the upper left-hand side they’re fairly
complex formulations. All of them had guarana as their natural
source of caffeine. So, we also utilize
guarana as a comparator
in the study. And so you’ll notice that at the bottom
of each column there is some
numbers in red. And so the first number is just the amount
of caffeine per capsule. And then the second is
the amount of caffeine you would consume
if you ingested that product per
label recommendations over a 24 hour period.
All right. And so the amounts range
from anywhere from like 500 milligrams
of caffeine to well over a gram. And so the way the study
was set up is we looked at 12 healthy
male adults. And they were randomized
for a supplement sequence over a six month period. And there was active
phases and a wash — and a two week washout
phase in between. And we monitored them
for heart rate, blood pressure,
and EKG activity. And so we monitor
EKG activity. We had them wear
a halter monitor under their shirts during the active
phases of the study as well as during some
of the washout phases. Right. And so not
too surprisingly given the quantities
of caffeine that are in these
products as well as some of the other natural
sympathomimetics, we saw significant elevations in —
excuse me — in systolic as well as
diastolic blood pressure and certainly
heart rate. But during the active
phases of the study we saw a lot more
abnormal EKG activity than we did
during the — during
the washout phases. And so nothing to get
too concerned about but nevertheless
we saw some, you know,
extra runs of V-tach, a few inverted t waves,
things like that. And of course not too
surprisingly there was a lot of complaints
of insomnia and anxiety
and nervousness. And there was a couple
of products caused a lot of nausea
and vomiting. And that a little bit
concerned us. And so when we were
analyzing the products for caffeine content
two of the products literally ran us
out of the lab they stunk so bad. And so my technician
says “You know, we may have a bacterial
contamination here.” And sure enough
we sent the products down to the National
Center for — National Center for
Toxicological Research which is also
an FDA region laboratory in Arkansas. And sure enough
two of the products were loaded with
some bacillus species, levels like 4
x 108 colony-forming units per gram, so a substantial number, one of which
was Bacillus cereus which is a known
human pathogen. So I felt really bad
about subjecting my guys to those things but, you know,
we didn’t know. I mean it wasn’t on
the label, has Bacillus cereus. I mean they just didn’t
do that, you know. So the bottom line
is that although these products
may be ephedra-free they may not necessarily
be trouble free. And so another —
and with regards to the whole
pharmacodynamic herb/drug
interaction mechanism, another product that we
run across on occasion is licorice root
extract. Now we’re not talking
about licorice candy. There’s not enough
of the compounds in licorice candy
to do anything. But a lot of dietary
supplements, particularly weight
loss supplements, will have licorice
root extract as one of
their components. And licorice root
has some interesting phytochemicals, one of which is called
glycyrrhizic acid. And when glycyrrhizic
acid is consumed it’s metabolized
to an active metabolite called
glycyrrhetinic acid. And what these two
compounds do is they inhibit
an enzyme called 11-beta-hydroxysteroid
dehydrogenase. Okay. Well,
what does that do? Well, that normally
converts cortisol to cortisone. And so when you inhibit
that enzyme you have higher
cortisol levels. And cortisol has
a higher mineralic corticoid effect and so you have
a tendency to retain sodium, lose potassium. And invariably if you’re
on a licorice extract for a long enough
period of time, and there have numerous
studies to show this, you will develop
hypertension. And so individuals that are trying
to lose weight but also may be on an antihypertensive
medication — if you’re taking one
of these products that has licorice
extract in it then it may actually
be negating the antihypertensive
effects of some of your
other medications. It may also —
it also may negate some of
the antiarrhythmic properties of certain
medications as well. All right. So those
are just two examples of the ephedra-free
supplements and the products that
contain licorice extract may have some
pharmacodynamic interactions. So you certainly
wouldn’t want to take particularly
ephedra-free supplements with prescription
stimulants like Adderall
or Ritalin. And of course you
wouldn’t want to take either of these
with regards to antihypertensive
medications. All right. So the next
major category of herb/drug
interactions are those that have
a pharmacokinetic mechanism. And what do
we mean by that? Well, basically
this is a situation where the phytochemicals
present in the — in the supplement
can either affect either the absorption, distribution,
metabolism, or excretion of a
conventional medication that may be consumed
with it concurrently. And what we’re talking
about specifically are situations where phytochemicals can
modulate the activity of human drug
metabolizing enzymes that are found
primarily in the gut and in the liver. These are things
like the cytochrome P450 enzymes, the UDP
glucuronosyltransferases, glutathione
transferases, sulfatases, and there’s just
a whole host of others. But they can also —
these phytochemicals can also
modulate transporters. Not only
the efflux transporters but also uptake
transporters. And these can also
be found in the liver and the gut
and also in the brain. All right. That’s one
of the reasons why we have
a blood/brain barrier is because we have
these efflux pumps that are in
the endothelial cells of the cerebral
vasculature that if a drug
diffuses into it, it can pump it back out.
All right. So we’ll look at some
examples of these. All right.
Now for those of you that may not be familiar with drug metabolism
to any great extent, there are a wide
variety of drug metabolizing enzymes
as I mentioned. One major category are
the cytochrome P450s. And of the
cytochrome P450s, these are
the principal ones that we find in humans. And the most important
one in humans is one called
cytochrome P4503A4. And the reason 3A4
is most important is because about half of all
conventional medications are metabolized
to some extent by 3A4. The next most important
one is like 2D6 followed by CYP2C9. Now just to kind of
give you an example utilizing this cartoon
to illustrate how modulating
the activity of these enzymes and
transporters in the gut and in the liver
can affect drug bioavailability. So our example here utilizes a drug
called felodipine. Felodipine is an
antihypertensive medication, a calcium
channel blocker. And so we’re
seeing there when it’s swallowed
eventually gets into
the small intestine where it comes
into contact with these enzymes
and transporters in the enterocytes
of the small intestine. And it just so happens
that felodipine is a substrate for 3A4. And 3A4 is highly
expressed in the gut. And so when felodipine
starts to go across the gut mucosa it’s metabolized
extensively. And looking at our
little diagram here, maybe only 30 percent
of our original dose gets across
the gut mucosa. From there it goes
to the liver through
the portal system. Gets exposed to even higher
concentrations of 3A4. And maybe only 15
percent of our original dose reaches
the systemic circulation to illicit a
pharmacologic response. Now if we take
a botanical — let’s say we take
a botanical with felodipine that inhibits 3A4. Classic example
is grapefruit juice. In that case less
of the felodipine is being metabolized
in the gut and so a larger
percentage reaches the
systemic circulation. And so in the case
with felodipine you may triple the bioavailability
of felodipine if you take it
with grapefruit juice because you’re
inhibiting that enzyme in the gut. On the other hand
if you were taking it with a supplement
like St. John’s wort that induces cytochrome
P4503A4 in the gut, then much more of
that drug’s going to be metabolized in the gut
and in the liver. And so instead of say
15 percent reaching the
systemic circulation maybe only five
percent or less. So those are kind
of the possibilities that can come about. And if you look at it
strictly from a pharmacokinetic
perspective and look at blood levels
of these particular drugs taken with
phytochemicals, let’s look at what
can happen. All right. So here we’ve got
classic pharmacokinetic
profiles. The yellow curve there
in the middle is –basically illustrates
a classic dose versus dosing regimens. So we’ve got a certain
dose of a medication given every, say
in this case, 24 hours. And so if you follow that consistently
you will reach what’s known
as a steady state. All right. And so those steady
state blood levels hopefully will fall within what’s known
as a therapeutic range. So you want your levels
above a minimum effective concentration but below a maximum
safe concentration. And so if the regimen is designed properly that’s what’ll happen. Now what you have
to understand is that those concentrations
at steady state, particularly for drugs
that are metabolized extensively
by the cytochrome P450 and other drug
metabolizing enzymes, those concentrations
at steady state are a function
of the activity of those enzymes.
Right. So — and the green — and the green curve
at the bottom is a situation
where we’ve induced the activity of those
enzymes such that when less drug gets
absorbed what drug — what does get absorbed gets metabolized
more extensively. Half-lives get shorter.
Less drug accumulates. And so it may render
the drug ineffective. On the other hand,
if we have a situation where we’re inhibiting
those cytochrome P450s or other drug
metabolizing enzymes, then more drug
gets absorbed. The half-lives
get longer. More drug accumulates. And you might have
some toxic manifestations.
All right? So this is the kind of
spectrum of possibilities with regards to these pharmacokinetic
herb/drug interactions. All right. So let’s look
at some examples. Far and away the most
problematic botanical with regards
to seriously clinically relevant
herb/drug interactions is St. John’s wort. Now high quality
St. John’s wort is also a fairly
decent antidepressant. In fact, several
studies have shown that it’s as effective
as a tricyclic — the tricyclic
antidepressants and even
the selective serotonin reuptake inhibitors. However it’s notorious
for causing herb/drug interactions. Now back in the late 90s we were one of
the first groups to prospectively start
to prospectively study a lot of the very
popular botanicals with regard
to their ability to modulate human
drug metabolism. And one of the very
first ones we looked at just happened to be
St. John’s wort because it was
so popular at the time. And so what these two
diagrams show here are the effect
of a 30-day course of St. John’s
wort on the activity of that very important
enzyme 3A4 in humans. And so the blue circles
just represent before and after cases
for individuals. And the red lines
and circles just represent
the average values. And so not only — we did studies
in a young cohort as well as
an elderly cohort. And in both instances we saw about
a hundred percent increase in the activity
of the enzyme which was quite
surprising to us. We almost kind of
scratched our head and said is this —
is this real? But nevertheless
it was what it was. And so you might
ask yourself well okay, so what?
You saw an increase in the activity
of the enzyme. Is that clinically
relevant? And so literally
a couple of weeks after we finished
this young cohort study I got a call from one
of our transplant surgeons at our transplant center
in Little Rock. And he calls me up
on the phone and says “Hey Gurley, man, I know you work with
that herbal crap. I’ve got a question
for you.” He actually used a
little harsher expletive than “crap” but it had the same
number of letters. So he said “Do you think
St. John’s wort would interfere
with cyclosporine?” And let me tell you
a little about cyclosporine. Cyclosporine is an
immunosuppressive drug that literally
revolutionized solid organ transplants. And it has a narrow
therapeutic window. So if the levels
are too low you may — you may risk
losing the graft. You may reject it. If the levels
are too high you run the risk
of kidney damage. But cyclosporine is also
a substrate for 3A4 as well as one of these
important efflux pumps called p-glycoprotein.
So keep that in mind. So I said “So do you
have transplant patients on cyclosporine
and St. John’s wort?” He goes “Yeah.”
And I said “Huh.” I said “I bet
the cyclosporine levels are really low.” And there was a long
pause on the phone. And he goes “Yeah,
how did you know that?” And so I want to
show you what this is. So this is
the cyclosporine trough
concentration profile for a 28-year-old
white female who was five years
post-kidney transplant. And because cyclosporine has a narrow
therapeutic window she’d have to come to
the clinic once a month and have her cyclosporine
levels drawn. And so for the longest
time you can see there that her levels were within
the desired range. But around
Christmas time in 1999 her cyclosporine levels
started to plummet. And so she was already
on 100 milligrams twice a day and they started —
and they were — they were like well
this is odd. And they started
bumping her dose up and then asking her “Are
you being compliant? Are you taking any
other medications?” “I am taking
my medications. I’m not taking
anything else.” Couldn’t figure out
what was — the levels just
kept going down. Finally she started
to show signs of acute rejection. This really got
everybody in a bit of a tizzy. And finally she revealed
to the dietitian on the transplant team “Well you know I’ve been
taking this St. John’s wort because I was
a bit depressed. You think that might
have — you might have some — this might be what’s
causing all the angst with the transplant
surgeons?” And that’s what prompted
the call to me. And so unfortunately —
well, so once they got her off
the St. John’s wort she was already on high
doses of cyclosporine. Her cyclosporine levels
kind of skyrocketed. They finally got them
back under control. Unfortunately her
acute rejection devolved into chronic rejection
and she lost her graft so she got back
on dialysis and back on
a transplant list. And this is just
one of four cases that happened in
our transplant center. Not all of them
lost their graft but all of them were
adversely affected by St. John’s wort. And so when we published
that case series in 2000, literally just
a few weeks and a couple months
after that there were
other transplant centers from around the world
reported the same thing, that St. John’s
wort taken by their patients
were causing not only the kidney
transplant rejection but also heart and liver
transplant rejection. So this interaction was especially
clinically relevant. So what is it about
St. John’s wort that makes it
so problematic? Well, remember
that little compound I mentioned earlier,
hyperforin? Well, hyperforin
is a unique phytochemical found
in St. John’s wort. And here’s
the structure of it. And it’s really
interesting because what hyperforin does, without getting
into a lot of the molecular
pharmacology, it turns on the genes for these enzymes
and transporters. It binds to
a transcription factor called PXR. And so when
it binds to PXR, PXR goes to the
nucleus of the cell and turns on the genes for these enzymes
and transporters. And it just so happens
that hyperforin is the most potent
ligand for PXR ever discovered. Prior to that we were
always concerned about rifampin. Rifampin is a classic
anti-tuberculosis drug and it’s notorious
for its ability to turn on these drug metabolizing
enzyme genes. And it’s a — it’s a ligand
for PXR as well but not nearly as
potent as hyperforin. All righty. Now I mentioned
the efflux pump. And so there’s a very
important efflux pump called p-glycoprotein. And so a lot of drugs
are also substrates for p-glycoprotein. And a classic one is
a drug called digoxin. And digoxin has a narrow therapeutic window
as well. It’s not used as much
as it used to — used to be used for
congestive heart failure but nevertheless
it’s a classic substrate for p-glycoprotein. And we did some studies
looking at effect of St. John’s
wort and rifampin on digoxin
pharmacokinetics. And so in both
of these curves here the black squares just represent
digoxin by itself. And the one on the left
is digoxin plus 600 milligrams
of rifampin a day. And so the green circle is just to show you the
area under the curve. And that’s dramatically
reduced with 600 milligrams
of rifampin. But over on the right is with hyperforin
or St. John’s wort. And we can see about
a similar reduction in the area
under the curve but there’s just
24 milligrams of hyperforin. All right, so it just
goes to show you how potent
that stuff can be. All righty.
So again the reason this is important
is because 3A4 and p-glycoprotein
are responsible for the metabolism
and transport of about, oh goodness, over half of all conventional
medications. And as I mentioned,
hyperforin appears to have some role in the anti-depressive
properties of St. John’s wort. And for the longest
time St. John’s wort was standardized
to another compound found in it
called hypericin because hypericin is
really easy to measure. All right. Hyperforin is quite difficult
to measure. It’s heat and light
sensitive. But — so oftentimes if
you knew the hypericin content that didn’t
really tell you anything about the hyperforin
content. Now, however, most St.
John’s wort products are standardized
to hyperforin. And the reason for that
comes to be shown here. So, we analyzed several
brands of St. John’s wort back in the day for both hyperforin
and hypericin content. And because they were
all standardized to hypericin you can see that on
the far right-hand side there most of
the hypericin content is pretty consistent. But look at the
hyperforin content. It’s all over the map, from as little
as one milligram almost to 14
milligrams per gram. All right.
But look at product A. There’s two different
lots of product A. And the hyperforin
content varied by almost a factor of four. Right. Now when you
start to get around levels of hyperforin around 10 milligrams
per gram you have some
significant induction of those enzymes
and transporters. So you can see
certain products were more problematic
than others simply because of
the hyperforin content. And this is
pretty consistent with just about
any phytochemical in any dietary
supplement. There’s a lot
of variability not only
among manufacturers but sometimes in
between lot numbers. All right. So again St. John’s wort
turns on 3A4. It turns on several
other cytochrome P450s as well as the efflux
pump p-glycoprotein and several other
efflux transporters. We saw how it affects
cyclosporine. We saw how
it affects digoxin. It makes the
anticoagulant warfarin less effective. There have been a lot
of miracle babies associated with the use
of St. John’s wort because it enhances
the metabolism of birth control pills. And it’s just
a partial list here. Even cancer
chemotherapeutic agents are adversely affected
with St. John’s wort. So you can certainly see
that the consequences are quite numerous because it renders
most drugs ineffective. Now just the opposite
of St. John’s wort is goldenseal. All right. And so
goldenseal is oftentimes used to prevent colds and upper respiratory
tract infections. But a lot of folks
like to use goldenseal to mask the results
of urine drug screens. And it’s quite effective for certain
drugs of abuse but it makes other
drugs of abuse easier to detect. So if you’re going to be
abusing medication — illicit medications and you want to use
goldenseal you damn well better know how that
stuff’s metabolized because
it may get you — it may get you
put in the pokey. All right. So, but the
thing about goldenseal is that it’s just the opposite
of St. John’s wort. It inhibits some
of these very important drug metabolizing enzymes
and transporters. And so here’s just some
data from a few studies we did several years ago looking at the effects
of goldenseal on these two important drug
metabolizing enzymes, 3A4 and 2D6. And we saw about
a 40 percent reduction in the activity
of those enzymes. Now instead of showing
you a modern day example of an herb/drug interaction
with goldenseal, I’m also
a Civil War historian but also
really interested in Civil War medicine. And so when I ran —
well, before I get into that let me just talk
a little bit about what actually
is in goldenseal that causes it
to be problematic. And so I’ll hold off
on my example. There are two compounds
in St. John — excuse me, in goldenseal that makes
it problematic. A compound
called hydrastine and another one
called berberine. All right. And by inhibiting
these two enzymes, 3A4 and 2D6 — those are the two
most important drug metabolizing enzymes
in humans. So you can see
the ramifications there. So here’s hydrastine
and berberine. All right.
And so you’ll notice that I’ve got one
portion of the molecule enclosed by this
broken circle. And that part of
the molecule is called a methylenedioxyphenyl
functional group. And the reason
I have it circled is because that’s the
portion of the molecule that interacts with the
enzyme to shut it down. These are what’s known
as mechanism-based inhibitors. So when these things
are metabolized by cytochrome P4503A4 they bind to — they bind to the enzyme
and shut it down. And the only way
you can overcome that is to make new enzyme.
All right. So it takes quite a long
time for that to happen. All righty. Now here’s my example.
All right. So when the Civil War broke out the
federal authorities blockaded all
the Southern ports. And it stopped
the influx or the importation
of quinine. And quinine was
the miracle drug of the mid-19th
century America because a lot of bugs —
a lot of folks, particularly in
the South, had malaria and quinine
was the only thing that was effective
in treating malaria. And so the Confederate
medical department put out an edict to all its surgeons
in the field to try to find
some indigenous plant in the South that could be used
as a quinine substitute. And there was
this great effort that went on
the whole war. They never found a good
substitute for quinine but they did find that
if you took quinine, what little
quinine you had, with goldenseal
you didn’t have to take as much quinine and the effects
lasted longer. And the reason for that
is because quinine is a 3A4 substrate. So I thought that
was really cool when I ran across that. So anyway, there’s —
so this is actually a beneficial
herb/drug interaction that was being utilized
150 years ago although they just
didn’t know why it was going on.
All right. So now with regards
to these phytochemicals that have these
methylenedioxyphenyl functional group,
these things are ubiquitous
in the plant kingdom. And the reason for that
is because these phytochemicals that have these
functional groups are really
good insecticides. All right. And that’s
how plants prevent bugs from chewing
on them and stuff. They make these
really cool — these cool
phytochemicals, many of which have these
methylenedioxyphenyl functional groups. Well, there’s another
one that we’re probably all familiar with
and that’s black pepper. And so black pepper
has a group of compounds called piperamides. Now don’t worry
about putting — garnishing your food
with black pepper if you’re going to get
some kind of drug interaction because it’s not
going to happen. There’s not enough — there’s not enough
of these piperamides in just ground up
black pepper. However, in a lot of
weight loss supplements you will see
the purposeful addition of black pepper extract. And the reason for that
is to inhibit drug metabolizing
enzymes in the gut so other phytochemicals can be more
readily absorbed. All right. So this
is just an example of the effect of black pepper extract
on one of the — on one of the anti-HIV medications
called Nevirapine. Nevirapine is
a non-nucleoside reversed transcriptase
inhibitor, has a real nasty
side effect profile. And so here you can see
the lower curve is just Nevirapine
by itself. The upper concentration
time profile is Nevirapine plus
black pepper extract. You can see
a tremendous increase in the area
under the curve and so that
would likely increase the side effect
profile of Nevirapine. All righty.
Continuing on with our methylenedioxyphenyl
theme, there’s another plant that’s getting
a lot of popularity. You’re starting
to see it being used in a lot of weight
loss supplements. And that’s Schizandra
chinensis. Now these are just a few
of the phytochemicals found in schizandra but you’ll notice
that all of them have this
methylenedioxyphenyl functional groups. And yes,
as you might expect, these things can inhibit
very important drug metabolizing enzymes,
particularly 3A4. So here’s another one, a
drug called Tacrolimus. Tacrolimus has kind
of taken over where cyclosporine
left off. It’s used to — it’s an
immunosuppressive drug used in some
organ transplants. And it has a narrow
therapeutic window as well. And so the broken line
there Iis just Tacrolimus’ area
under the curve by itself and the other
one is Tacrolimus plus schizandra extract. And so here again
you can see the tremendous increase in the area
under the curve. And so this would be
another clinically relevant herb/drug
interaction. All right. Now what’s
really cool about these
methylenedioxyphenyl functional groups is that when you
take them acutely they’re very potent
inhibitors of a lot of these
cytochrome P450 enzymes. But the longer you’re
on them it looks like they start to induce a lot of those
cytochrome P450s. And so you may have
this whole spectrum of situations where you make
toxicity initially and then
render medications ineffective the longer
you take them. So it’s
quite interesting. But nevertheless as long
as you’re not taking any other medications these are —
these are probably fine. But if you’re taking
other medication you better be careful. All right. Now another
one that’s quite interesting and that’s the effect
of green tea on Nadolol. And so here again if you
look at the curve there on the left
you’ll notice that it looks
like green tea lowers the area under
the curve for Nadolol. So you would think well
okay well it’s inducing the metabolism
of Nadolol just like St. John’s
wort would. Unfortunately, Nadolol
is not metabolized. So what’s going on? Well just in this case
what’s happening is green tea is inhibiting
the uptake of Nadolol through some of these
uptake transporters that we find in the gut. All right.
And so green tea can certainly reduce
the activity of Nadolol. All right. And how
does that happen? Well there is a group
of compounds in green tea
called the catechins. And the catechins are
notorious for inhibiting a lot of these
uptake transporters. And it’s important
because green tea is one of
the most popular beverages in the world. And green tea is also a
very prominent component in a lot of weight
loss supplements. So we can be exposed
to high concentrations of some of
these catechins. All righty. A couple of others
and we’ll finish up. Resveratrol. You probably have
heard of resveratrol. It’s a compound
purportedly in red wine and grape skins
and such. And for the longest time
it was thought to be one of these
miracle supplements. But we are seeing now
that very high doses of resveratrol appear to inhibit
some important drug metabolizing enzymes,
particularly 3A4 but most importantly
one called 2C9. But it’s not
the resveratrol itself. It’s actually
a metabolite of resveratrol, the sulfate metabolite, that appears to be
the culprit here. And here’s an example
looking at the effects of resveratrol
on a drug that’s metabolized by
2C9 called diclofenac. And diclofenac’s
a really potent non-steroidal
anti-inflammatory drug and it has a fairly narrow
therapeutic window for non-steroidals. And here you —
here you can see the concentration time
profiles for diclofenac by itself and diclofenac
plus resveratrol. So again another example
of a probably clinically relevant herb/drug
interaction. Now you might say,
well my goodness, all these things
have a potential to cause some type of
significant interaction. That’s just not
the case. It looks like
the majority of the more
popular botanicals that are on the market
don’t appear to pose a significant risk for
herb/drug interactions. However, we’ve really only
scratched the surface with regards to the
number of these products that have been
evaluated prospectively in a clinical setting. Now the reason
that a lot of the more
popular botanicals don’t pose a significant
interaction risk is because a lot
of these phytochemicals have very poor
water solubility. They just don’t go into
solution to be absorbed. And then others that are
absorbed quite readily are metabolized extensively in the gut
and in the liver. And so they’re
systemic — their systemic levels
are really really low, sometimes nonexistent. However, their
metabolites are there and oftentimes
we may see some effects from their
active metabolites. All right. So the
dietary supplement manufacturers
recognize the fact that a lot
of these phytochemicals have very poor
oral bioavailability. And so there are unique
technologies that are being utilized to improve
their bioavailability, things like
incorporating them into liposomes, complexing them
with phosphatidylcholine into structures
called phytosomes, making self-emulsifying
drug delivery systems, incorporating them
as nanoparticles. And then as I mentioned
earlier just purposely adding natural
inhibitors of drug metabolizing
enzymes like piperine. All of these things
can improve the oral bioavailability of a lot of these
unique phytochemicals. The question is: All right, that might
certainly improve their efficacy
and/or effectiveness. But it also might make
them more problematic. Because heretofore
those drugs have been fairly — their bioavailabilities
have been very low. And now they may
be quite large. And who’s to say
that doesn’t increase their risk for herb/drug
interactions. We don’t know
because no one’s done any studies
for these yet. I’ve been trying
to get funding for that but that’s not —
been kind of difficult. Anyway, so to conclude
botanical supplements can indeed interact with conventional
medications. The interactions may be
either pharmacodynamic or pharmacokinetic
in mechanism. And it looks like
most of the popular botanicals
don’t pose a serious risk for
herb/drug interactions. We did illustrate some of the more
problematic ones. But again
a lot of the — a lot of these products haven’t been
evaluated in vivo. And again
these novel dosage forms
may be game changers for a lot of these
popular botanicals that at this point in their
traditional formulations don’t appear
to pose a risk. And with that
I’ll also leave some — leave you with some
information resources, some websites
about interactions, if you want to. And I’ll be happy to
entertain any questions. Thank you. [applause] That’s another reason
I like to come here. I always get
a standing ovation. [laughter]>>Cindy Davis:
We have time for two quick questions.>>Male Speaker:
I was wondering — I was wondering
how much do we know about the drug
metabolism enzymes
of the botanicals?>>Bill Gurley:
Where are you at? Okay, so ask
your question again. I was trying
to find you, I’m sorry. So this was
a great talk. So we know a lot
of the CYP450s for drugs obviously. I was wondering
how much do we know about the CYP450s and also the phase two
for the botanicals?>>Bill Gurley:
Great question. And so a lot of the — you’d be surprised at
how many phytochemicals are metabolized
by cytochrome P450s. A lot of the polyphenols
that you see in a lot of — undergo significant
conjugation. And so you’ll — it’s — the short answer
to your question is “significant.” A lot of phytochemicals
are metabolized through phase one —
through phase one reactions
via cytochromes or some of the others, but a lot of them
also undergo significant conjugation reactions
as well. In fact probably the
most common metabolites that you see
with regards to phytochemicals are either glucuronides
or sulfates. And it looks like
of those two a lot of the sulfates
also appear to be active
in many instances. So it’s
a great question. Yes, ma’am.>>Female Speaker:
I have a comment and a question. Back around 2000, when there were
some small studies showing that St. John’s wort affected the therapeutic window
of protease inhibitors, the evidence was very — was — there wasn’t
a lot of evidence but it was so impressive
we had a clinic — a nutrition clinic
at a needle exchange and we pulled St. John’s wort out of all
of our formulas. I feel vindicated
in having done that.>>Bill Gurley:
Yes.>>Female Speaker:
My question is about licorice. And so licorice
is used a lot in anti-inflammatory
formulas. And there is —
and herbalists recognize that there is a problem
with glycyrrhizin and blood pressure. And so by removing
the glycyrrhizin from licorice it seems like
from your talk that it would
actually increase the
anti-inflammatory effect rather than decrease it.>>Bill Gurley:
I — of course –>>Female Speaker: I mean that
would suggest it.>>Bill Gurley:
Yeah, so glycyrrhizin — that’s not
the only phytochemicals in licorice
as you well know.>>Female Speaker:
Right, I know.>>Bill Gurley: Yeah.
So when you take the — when you take
those components out of licorice you certainly take
away that issue with regards
to the hypertensive aspects of it. Whether or not
that improves the anti-inflammatory
aspects of licorice, you may be a better —
you may — you may be more familiar with that literature
than I am. But I would
not be surprised.>>Female Speaker:
There isn’t any — there isn’t any
literature on that.>>Bill Gurley:
Okay. Well then there we go.
So the jury’s still out.>>Female Speaker:
But it does seem like it would increase the
production of cortisol. But I’m just guessing.
And one quick comment. Now I understand
why there is a traditional use
of turmeric and black pepper
together as an anti-inflammatory.>>Bill Gurley:
Exactly. Yeah.>>Cindy Davis:
So I am going to ask people that still have
questions to come up and please address
the speaker. And we’re actually —
let’s give appreciation and then we’re
on lunch break. [applause]

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