Clin Pharmacokinet 2003; 42 (13): 1071-1088

LEADING ARTICLE 0312-5963/03/0013-1071/$30.00/0

© Adis Data Information BV 2003. All rights reserved.

Dietary Effects on Drug Metabolism

and Transport
Robert Z. Harris,1 Graham R. Jang1 and Shirley Tsunoda2
1 Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks,
California, USA
2 General Clinical Research Centre, University of California at San Francisco, San Francisco,
California, USA

Abstract Metabolic food-drug interactions occur when the consumption of a particular

food modulates the activity of a drug-metabolising enzyme system, resulting in an
alteration of the pharmacokinetics of drugs metabolised by that system. A number
of these interactions have been reported. Foods that contain complex mixtures of
phytochemicals, such as fruits, vegetables, herbs, spices and teas, have the
greatest potential to induce or inhibit the activity of drug-metabolising enzymes,
although dietary macroconstituents (i.e. total protein, fat and carbohydrate ratios,
and total energy intake) can also have effects. Particularly large interactions may
result from the consumption of herbal dietary supplements.
Cytochrome P450 (CYP) 3A4 appears to be especially sensitive to dietary
effects, as demonstrated by reports of potentially clinically important interactions
involving orally administered drugs that are substrates of this enzyme. For
example, interactions of grapefruit juice with cyclosporin and felodipine, St
John’s wort with cyclosporin and indinavir, and red wine with cyclosporin, have
the potential to require dosage adjustment to maintain drug concentrations within
their therapeutic windows. The susceptibility of CYP3A4 to modulation by food
constituents may be related to its high level of expression in the intestine, as well
as its broad substrate specificity. Reported ethnic differences in the activity of this
enzyme may be partly due to dietary factors.
Food-drug interactions involving CYP1A2, CYP2E1, glucuronosyltransfer-
ases and glutathione S-transferases have also been documented, although most of
these interactions are modest in magnitude and clinically relevant only for drugs
that have a narrow therapeutic range. Recently, interactions involving drug
transporters, including P-glycoprotein and the organic anion transporting poly-
peptide, have also been identified. Further research is needed to determine the
scope, magnitude and clinical importance of food effects on drug metabolism and
transport.

The effects of food on pharmacokinetics have ministered under fasted conditions. A multitude of
been well documented.[1-5] Numerous drugs display mechanisms are responsible for food effects, includ-
clinically important differences in pharmacokinetics ing delayed gastric emptying, solubilisation of drug
when administered with food relative to when ad- by food and digestive fluids, complexation of drug
1072
with food components, alterations in hepatic blood
flow and modulation of drug-metabolising enzymes
by constituents of food. The goal of this manuscript
is to review the current literature regarding dietary
effects on drug metabolism and transport. Although
this topic was reviewed relatively recently,[3] our
knowledge base has expanded considerably over the
past 5 years.
Metabolic food-drug interactions are akin to met-
abolic drug-drug interactions. Both types of interac-
tions occur when the administration or ingestion of
one xenobiotic (an inducer or inhibitor) modulates
the metabolism and pharmacokinetics of another
xenobiotic (the substrate drug). Many metabolic
drug-drug interactions have been documented.
These interactions can result in tremendous variabil-
ity in pharmacokinetics, with changes in drug con-
centrations of over 10-fold being reported.[6-9] Be-
cause the majority of xenobiotics that enter the body
are components of the diet rather than pharmaceuti-
cal agents, it is reasonable to predict that certain
dietary constituents will also be capable of modulat-
ing drug metabolism. Just as metabolic drug-drug
interactions can have dramatic clinical conse-
quences, resulting in severe adverse events or thera-
peutic failure,[9-11] metabolic food-drug interactions
also have the potential for such effects.
This review focuses primarily on the effects of
dietary constituents on specific drug-metabolising
enzymes. Over the past decade, great advances have
been made in identifying the cytochrome P450s
(CYP) and other enzymes responsible for the meta-
bolism of drugs.[12] A list of the major enzymes and
transporter systems involved in drug disposition,
along with some of their substrates, is presented in
table I. Once a substance, whether a drug or constit-
uent of the diet, is identified as an inhibitor or
inducer of a particular enzyme, it is often reasonable
to assume that it is capable of affecting the elimina-
tion of all drugs that are metabolised by that
enzyme. For example, if administration of a sub-
stance is found to increase the clearance of caffeine,
a compound specifically metabolised by the enzyme
CYP1A2, this substance will likely also increase the
clearance of other drugs that are primarily eliminat-
© Adis Data Information BV 2003. All rights reserved.
Harris et al.
Table I. Enzymes and transporters involved in human drug
disposition[13-18]
Enzyme or Example substrates
transporter
CYP1A2 Caffeine, clozapine, fluvoxamine, imipramine,
theophylline
CYP2C9 Ibuprofen, diclofenac, tolbutamide, (S)-warfarin
CYP2C19 (S)-Mephenytoin, omeprazole, proguanil
CYP2D6 Carvedilol, desipramine, dextromethorphan,
thioridazine
CYP2E1 Ethanol, chlorzoxazone, halothane, enflurane
CYP3A4 Cyclosporin, terfenadine, midazolam,
erythromycin, many HIV protease inhibitors,
calcium channel antagonists and statins
UGTs Paracetamol (acetaminophen), oxazepam,
lorazepam, zidovudine, morphine
P-glycoprotein Cyclosporin, digoxin, fexofenadine, loperamide
OATPs Fexofenadine, digoxin, pravastatin
CYP = cytochrome P450; OATP = organic anion transporting
polypeptide; UGT = uridine diphosphate glucuronosyltransferase.
ed by CYP1A2, including theophylline and fluvox-
amine. By focusing on how specific enzyme sys-
tems are affected by food, potentially valuable
generalisations can be made based upon the results
of a few well-designed clinical studies. The clinical
significance of a particular interaction must be as-
sessed individually, however, based upon the mag-
nitude of the interaction and the therapeutic window
of the compound affected.
1. Cytochrome P450 (CYP) 3A4
CYP3A4 is involved in the metabolism of nu-
merous drugs, including cyclosporin, midazolam,
many calcium channel antagonists, HMG-CoA re-
ductase inhibitors and HIV protease inhibitors.[19,20]
It has been estimated that this enzyme participates in
the metabolism of over 50% of all pharmaceutical
agents.[12] CYP3A4 is robustly expressed in large
quantities in both the liver and the gut wall,[21-23] and
appears to be involved in both systemic and presys-
temic metabolism.[24] The promiscuity of CYP3A4
with regard to its substrate specificity, along with its
high concentrations in the gut wall, suggest that it
has evolved to protect the body from potentially
toxic dietary xenobiotics. Therefore, the activity of
this enzyme may be particularly sensitive to modu-
lation by components within food.
Clin Pharmacokinet 2003; 42 (13)
Dietary Effects on Drug Metabolism and Transport
A number of clinically important drug-drug inter-
actions involving CYP3A4 have been document-
ed.[7] Drugs that are clinically important CYP3A4
inhibitors include ketoconazole, itraconazole, dil-
tiazem, erythromycin, clarithromycin and
nefazodone.[13] These inhibitors can cause marked
increases in the plasma concentrations of drugs that
are CYP3A4 substrates. For example, ketoconazole
has been shown to cause 16-, 22- and up to 73-fold
increases in midazolam,[6] triazolam,[7] and
terfenadine[25] exposure, respectively. In addition,
CYP3A4 inducers, including phenobarbital and ri-
fampicin (rifampin), can decrease the circulating
concentrations of CYP3A4 substrates such as
ethinylestradiol,[26] resulting in contraceptive fail-
ure, and cyclosporin,[27] resulting in organ transplant
rejection. As discussed in the following paragraphs,
there are also numerous examples of metabolic in-
teractions involving modulation of CYP3A4 activity
by dietary components. It should be noted, however,
that caution should be exercised when making
generalisations regarding the effect of food on the
metabolism of CYP3A4 substrates, since this
enzyme appears to have multiple substrate-binding
sites that can be differentially affected by various
inhibitors.[28-30] Thus, the effect of food constituents
on CYP3A4 activity may be substrate-dependent.
1.1 Grapefruit Juice
Perhaps the best-characterised food-drug inter-
action involves inhibition/inactivation of CYP3A4
by grapefruit juice consumption. This interaction
has been previously reviewed in detail,[31-33] and is
briefly summarised below. Grapefruit juice has been
shown to increase concentrations, by up to 300%, of
a number of orally administered medications includ-
ing cyclosporin,[34-36] terfenadine,[37-39] midazo-
lam[40,41] and felodipine.[42,43] The mechanism of this
interaction is believed to involve both inhibition and
inactivation of CYP3A4 by dihydroxybergamottin
and other coumarin derivatives found in grapefruit
juice, although bioflavonoids such as naringin, nar-
ingenin, quercetin and kaempferol may also play a
role. Because inactivation appears to play a role in
the interaction, long-term consumption of grapefruit
© Adis Data Information BV 2003. All rights reserved.
1073
juice may cause a greater magnitude and duration of
effect than that which occurs after consumption of a
single serving.[44] In general, interactions appear to
be more marked and prevalent for drugs that under-
go significant intestinal metabolism,[44-46] although
long-term consumption may also have some effect
on hepatic metabolism.[47] It should be noted that
modulation of the activity of the drug transporter P-
glycoprotein may play a role in some of the observ-
ed food-drug interactions involving CYP3A4 sub-
strates (see section 5).
1.2 Orange Juice
Consumption of most types of orange or tanger-
ine juice does not appear to alter CYP3A4 activity in
vivo, as evidenced by a lack of interaction with
midazolam.[48,49] However, orange juice made from
Seville oranges appears to be more grapefruit juice-
like and can affect the pharmacokinetics of CYP3A4
substrates. For example, consumption of a single
240mL serving of Seville orange juice has been
shown to result in a 76% increase in felodipine
exposure, comparable to what is observed after
grapefruit juice consumption.[48] Presumably, the
mechanism of this effect is similar to that of
grapefruit juice-mediated interactions, as Seville
oranges contain significant concentrations of
dihydroxybergamottin, a bioflavonoid found in
grapefruit juice that is not found in other types of
orange juice.[50]
1.3 Wine
Red wine has recently received a great deal of
attention based upon purported health benefits asso-
ciated with its consumption. Several studies have
demonstrated cardiovascular benefits to drinking
moderate amounts of red wine.[51-53] The so-called
‘French Paradox’ refers to the fact that Frenchmen
have a 36% lower mortality rate from cardiovascular
causes compared with their counterparts in the US,
despite their higher intake of saturated fat and higher
prevalence of risk factors such as hypercholesterol-
aemia, diabetes and hypertension.[54] These benefits
of red wine consumption are sometimes attributed to
its high content of antioxidant molecules. Like
Clin Pharmacokinet 2003; 42 (13)
1074
grapefruit juice, red wine contains a complex mix-
ture of molecules including flavonoids and other
polyphenols.[55] These large electron-rich molecules
are likely to be substrates of CYP3A4 and could
potentially inhibit the enzyme. Due to the extensive
consumption of wine world-wide, metabolic inter-
actions resulting from red wine consumption could
be of great clinical importance.
An in vitro study has demonstrated that red wine
solids inhibited CYP3A4, as measured by 6β-hy-
droxylation of testosterone, in a time- and concen-
tration-dependent manner.[55] In contrast, white
wine solids did not affect CYP3A4 activity, presum-
ably because white wine is lacking in the flavonoids
and other antioxidant molecules that are present in
red wine. Subsequent studies have demonstrated
that a predominant component of red wine, trans-
resveratrol, is a noncompetitive inhibitor[56] and
mechanism-based inactivator[57,58] of CYP3A4, al-
though other compounds found in red wine probably
contribute to the observed inhibition.[57,58]
Because in vitro data do not always accurately
predict in vivo effects, a study to assess the effect of
acute consumption of 340mL (12 ounces) of red
wine on the pharmacokinetics of the CYP3A4 and
P-glycoprotein substrate cyclosporin was initiat-
ed.[59] Surprisingly, instead of causing an increase in
cyclosporin exposure, which would be expected for
a CYP3A4 inhibitor, acute red wine consumption
caused a statistically significant 30% decrease in the
area under the plasma concentration-time curve
(AUC) of cyclosporin and a 40% decrease in the
maximum plasma concentration (Cmax), with no
change in half-life. This decrease in cyclosporin
exposure after a single administration of red wine is
of a magnitude that could be clinically important
and may result in acute organ rejection. The mecha-
nism for the decrease is currently unknown, al-
though it is possible that there is a direct binding
interaction (i.e. complexation) between cyclosporin
and constituents in red wine that limits solubility
and lowers the extent of absorption. It is also poss-
ible that the decrease in exposure is due to stimula-
tion of the activity of P-glycoprotein or another
© Adis Data Information BV 2003. All rights reserved.
Harris et al.
efflux drug transporter, although in vitro data sug-
gest that P-glycoprotein activity is not affected by
red wine (LZ Benet, personal communication).
In a follow-up study, the effect of prolonged
administration (340mL per day for 7 days) of red
wine on cyclosporin pharmacokinetics was as-
sessed.[60] In contrast to the design used in the sin-
gle-dose study,[59] for this assessment cyclosporin
was administered 12 hours after red wine consump-
tion, greatly reducing the chance that an observed
interaction would be due to acute, reversible, inhibi-
tion of intestinal CYP3A4 or complexation of red
wine and cyclosporin. Consistent with the inactiva-
tion that was observed in vitro, it was found that
prolonged administration of red wine resulted in a
13% increase in mean cyclosporin exposure, with
one subject showing an 82% increase. Also, consis-
tent with the in vitro data, neither single-dose nor
multiple-dose consumption of white wine had a
notable effect on the pharmacokinetics of cyclospo-
rin, suggesting that the effects observed were due to
constituents in red wine and not a result of alcohol
consumption. In addition to these red wine-cyclo-
sporin studies, it was recently reported that a single
administration of red wine caused an average in-
crease in cisapride AUC of 15%, although this in-
crease was not statistically significant.[61] Important-
ly, one of the twelve subjects displayed a 2-fold
increase in cisapride exposure, indicating that the
magnitude of the interaction can vary across individ-
uals. The authors suggested that individuals with
high intestinal CYP3A4 content may experience
clinically relevant drug interactions with red wine.
Therefore, it appears that the inhibition of
CYP3A4 by red wine that occurs in vitro can, to
some extent, occur in vivo, and could lead to clini-
cally important interactions in particularly suscepti-
ble individuals. It should be noted that different
types of wine displayed different inhibitory poten-
tials towards CYP3A4 in vitro,[55] suggesting that
the magnitude of the effects of red wine on the
pharmacokinetics of CYP3A4 substrates may be
dependent on both the amount and type of red wine
consumed.
Clin Pharmacokinet 2003; 42 (13)
Dietary Effects on Drug Metabolism and Transport
1.4 St John’s Wort
The use of nonprescription herbal dietary supple-
ments such as St. John’s wort, gingko biloba, Ma
huang and milk thistle appears to be dramatically
increasing,[62] in part due to their addition to bever-
ages and sports/nutrition bars. Consumption of
many of these supplements can result in exposure to
large amounts of a complex mixture of xenobiotics.
Thus, these agents may be more appropriately con-
sidered drugs rather than foods. Because they are not
regulated as rigorously as are drugs, clinically im-
portant drug interactions involving herbal supple-
ments may not be as readily detected or document-
ed. Interactions between herbal medicines and pre-
scribed drugs have recently been reviewed.[63]
St John’s wort (Hypericum perforatum) is a herb-
al medicine commonly taken for the treatment of
depression. It is frequently prescribed in Europe, but
its use is not regulated in the US. St John’s wort
extract contains a complex mixture of molecules
including the compounds hypericin and hyperforin.
Recently, a number of reports have indicated that
coadministration of St John’s wort with cyclosporin
can result in large decreases in cyclosporin concen-
trations, sufficient to cause organ rejection.[64-66] In
one report, two cases of acute heart transplant rejec-
tion were reported in patients who had previously
been stabilised on cyclosporin and had initiated self-
medication with St John’s wort.[65] In both cases,
dramatic decreases in cyclosporin concentrations
were believed to be responsible for the rejection. In
another report,[67] St John’s wort caused cyclosporin
concentrations to drop by a mean of 47% (range
33–62%) in 30 kidney transplant recipients, necessi-
tating a mean 46% (range 15–115%) increase in
dosage. After discontinuation of St John’s wort,
cyclosporin blood concentrations rebounded. These
results suggest that St John’s wort is a potent inducer
of CYP3A4. Consistent with CYP3A4 induction, it
has also been reported that treatment with St John’s
wort reduced the AUC of the HIV protease inhibitor
and CYP3A4 substrate indinavir by 57%.[68] In addi-
tion, a recent abstract suggests that St John’s wort
may cause a clinically important increase in the oral
clearance of the contraceptive norethindrone.[69] It
© Adis Data Information BV 2003. All rights reserved.
1075
was also found that four days of St John’s wort
therapy caused a decrease in the AUC of alprazo-
lam, another substrate of CYP3A4, though this de-
crease was not statistically significant.[70]
Similar to the grapefruit juice interaction, the St
John’s wort interaction may be more profound with
orally administered compounds that undergo signif-
icant presystemic metabolism. A recent study differ-
entiated between the inductive effects of St John’s
wort on intestinal and hepatic CYP3A4 activities.[71]
Long-term administration of St John’s wort was
shown to cause a >50% decrease in midazolam
AUC after oral administration (as a result of changes
in the activity of hepatic and intestinal CYP3A4),
but midazolam AUC decreased by only 20% after
intravenous administration (as a result of changes in
hepatic enzyme only). It appears that the induction
of CYP3A4 by St John’s wort occurs via the preg-
nane-X receptor,[72] which is believed to mediate
CYP3A4 induction by many pharmaceutical agents.
Long-term administration of St John’s wort did not
affect the activities of CYP2C9, 1A2 and 2D6, as
assessed by tolbutamide pharmacokinetics, and caf-
feine and dextromethorphan urinary metabolic ra-
tios, respectively.[71] As described in section 5.2,
long-term administration of St John’s wort may also
affect the activity of P-glycoprotein.
Taken together, the data suggest that St John’s
wort is a potent inducer of CYP3A4. In addition to
the interactions that have been reported, St Johns
wort treatment would likely cause clinically impor-
tant decreases in the exposure of other CYP3A4
substrates that have narrow therapeutic indices, in-
cluding immunosuppressives and antiepileptic
agents.
1.5 Garlic
In vitro, it was demonstrated that garlic has an
inhibitory effect on CYP3A4,[73] suggesting that
garlic consumption may result in an increase in the
circulating concentrations of CYP3A4 substrates.
However, clinically it was demonstrated in healthy
volunteers that administration of two garlic caplets
twice a day resulted in an approximate 50% de-
crease in exposure to saquinivir, an HIV protease
Clin Pharmacokinet 2003; 42 (13)
1076
inhibitor metabolised primarily by CYP3A4.[74]
After a 10-day washout period, saquinivir exposure
returned to 60–70% of baseline. This result suggests
that garlic consumption may markedly induce
CYP3A4. As already described, CYP3A4 induction
can result in clinically important interactions with a
number of pharmaceutical agents.
1.6 Diet as a Potential Cause of
Ethnic Differences
There have been numerous reports of ethnic dif-
ferences in the pharmacokinetics of CYP3A4 sub-
strates, although the data have been conflicting. It is
possible that dietary factors contribute to some of
the observed differences across studies. For exam-
ple, it has been reported that the mean nifedipine
exposure after oral administration to South Asian
subjects who consumed a Bangladeshi diet was
more than 2-fold higher than that in Caucasian sub-
jects living in Britain.[75] Comparable differences in
nifedipine pharmacokinetics between Asians and
Caucasians in separate studies were also report-
ed.[76,77] In contrast, a marked difference in the
pharmacokinetics of triazolam, another CYP3A4
substrate, was not observed between South Asians
who consumed a Western diet and Caucasians.[78]
Thus, it is possible that the ethnic difference observ-
ed in nifedipine pharmacokinetics is related to diet-
ary differences between the populations. However,
the conversion of Caucasians to a South Asian diet
did not appear to alter the pharmacokinetics of ni-
fedipine.[79]
It has been reported that African-Americans have
increased CYP3A4 activity relative to Caucasians,
as evidenced by lower cyclosporin bioavailabil-
ity.[79] Consistent with a contributing role of dietary
factors, this apparent ethnic difference in cyclospo-
rin pharmacokinetics between Caucasians and Afri-
can-Americans was not observed when diet was
controlled for 5 days.[80] In contrast, a recent study
found no difference in the pharmacokinetics of
midazolam between Caucasians and African-Ameri-
cans.[81] Finally, Mexican and Japanese subjects
were observed to have increased nifedipine[82] and
cyclosporin[83] bioavailabilities compared with those
© Adis Data Information BV 2003. All rights reserved.
Harris et al.
in European and North American subjects. The au-
thors suggested that dietary differences may account
for these ethnic differences in pharmacokinetics.
Taken together, the data suggest that ethnic differ-
ences in CYP3A4 activity may exist, which may be
partly due to ethnic differences in diet.
2. CYP1A2
CYP1A2 is primarily expressed in the liver and
plays a major role in the metabolism of numerous
human xenobiotics, including caffeine, clozapine,
imipramine and theophylline.[84] CYP1A2 is induci-
ble via activation of the aryl hydrocarbon receptor
by planar molecules such as heterocyclic amines and
polycyclic aromatic hydrocarbons, although recep-
tor-independent mechanisms may also contrib-
ute.[84] Another enzyme in this CYP subfamily,
CYP1A1, is primarily expressed and inducible in
the intestine and other extrahepatic tissues, and is
thus thought to play a comparatively minor role in
hepatic drug metabolism. As recently reviewed,[85]
the proton pump inhibitor, omeprazole, has been
shown to induce CYP1A2 in vitro and in vivo,
although clinically significant drug-drug interac-
tions as a result of this are scarce. In contrast, as
illustrated below, a number of diet-drug interactions
involving CYP1A2 induction by dietary constitu-
ents have been demonstrated.
2.1 Caffeine-Containing Beverages
Caffeine is considered a prototypical CYP1A2
substrate and has been frequently used as an in vivo
probe (via monitoring of salivary or urinary metabo-
lite ratios) to assess food effects on CYP1A2 ac-
tivity. In the rat, it is both a substrate and inducer of
CYP1A enzymes in the intestine and liver,[86-88]
suggesting that caffeine intake in humans may affect
the clearance of other drugs that are substrates of
CYP1A2.
To assess the effects of regular caffeine con-
sumption on CYP1A2 activity, eleven subjects con-
sidered ‘heavy’ (~250–525mg caffeine/day) coffee
drinkers abstained from the beverage for at least 21
days. The mean half-life of salivary caffeine (fol-
lowing coffee ingestion) after the abstinence period
Clin Pharmacokinet 2003; 42 (13)
Dietary Effects on Drug Metabolism and Transport
was prolonged by 17% relative to that at the initia-
tion of the study.[89] Although this modest change in
half-life was statistically significant, it should be
noted that half-life was unchanged in three and
shortened in one subject. Assuming that the 21-day
period was sufficient for the subjects’ CYP1A2
levels to return to baseline, these data suggest that
‘heavy’ caffeine consumption in humans may mod-
estly induce liver CYP1A2. To date, no other signif-
icant drug interactions resulting from CYP1A2 inhi-
bition or induction by caffeine have been reported.
2.2 Grapefruit Juice
As noted in section 1.1, naringin is one of many
grapefruit juice constituents that may contribute to
its in vivo inhibitory effects on CYP3A4. It is the
most abundant flavonoid in grapefruit juice and,
upon ingestion in humans, is converted in the
intestine to its aglycone, naringenin.[90] The latter
compound was reported to competitively inhibit
CYP1A2 activity in vitro with an inhibition constant
(Ki) in the range of 7–30 μmol/L.[91] Furthermore,
other components of grapefruit juice, the fura-
nocoumarins bergamottin and dihydroxybergamot-
tin, have been demonstrated to inhibit CYP1A2 in
vitro with 50% inhibitory concentrations (IC50) of
less than 1 μmol/L.[92] Collectively, these data sug-
gest that concomitant ingestion of grapefruit juice
could potentially alter the disposition of drugs that
are metabolised by CYP1A2.
In a randomised crossover design study with 12
subjects, the ingestion of 300mL grapefruit juice,
prior to and every 6 hours after caffeine administra-
tion, resulted in a 23% decrease in the oral plasma
clearance and 31% increase in half-life of caf-
feine.[91] It was noted that this extent of CYP1A2
inhibition by grapefruit juice was probably of limit-
ed clinical significance. In contrast with the effect
observed on caffeine metabolism, these investiga-
tors subsequently reported that concomitant inges-
tion of theophylline and 100mL grapefruit juice,
followed by consumption of 100mL of juice at 1
hour postdose and 200mL of juice at 4, 8, 12 and 16
hours postdose, had no effects on the oral pharmaco-
kinetics of theophylline.[93] The naringin concentra-
© Adis Data Information BV 2003. All rights reserved.
1077
tions in the juices used in the caffeine and theophyl-
line studies were similar. Potential reasons noted for
the observed grapefruit juice effects on caffeine but
not theophylline pharmacokinetics were: (i) a differ-
ence in naringin or naringenin disposition between
the two study groups (8 of 12 were female in the
caffeine study; all were male in the theophylline
study); (ii) a lower contribution of CYP1A2 to the
elimination of theophylline relative to caffeine; and
(iii) inclusion of smokers (who generally display
higher CYP1A2 levels) in the caffeine study.
Subsequently, other investigators have reported
that repeated ingestion of grapefruit juice did not
alter the pharmacokinetics and pharmacodynamics
of caffeine[94] or the steady-state pharmacokinetics
of the CYP1A2 substrate clozapine.[95] Thus, current
evidence suggests that grapefruit juice has limited
potential to alter the disposition of drugs that are
CYP1A2 substrates. If such interactions occur, they
would probably be modest and therefore of limited
clinical significance.
2.3 Grape Juice
In 12 subjects, the coadministration of a 0.9g oral
dose of phenacetin with 200mL of juice from Jufeng
grapes, the most prevalent type of grape in China,
resulted in an approximately 2-fold decrease in phe-
nacetin AUC, but no change in the AUC of its
metabolite, paracetamol (acetaminophen).[96] The
investigators suggested that these effects were due
to activation of CYP1A2, resulting in more exten-
sive first-pass hepatic extraction. Indeed, there is in
vitro evidence that CYP1A2 can be modulated via
apparent allosteric mechanisms, leading to enhanced
rates of metabolism.[97,98] Another proposed mecha-
nism for the interaction was prolonged phenacetin
absorption (the median time to peak concentration
[tmax] was modestly prolonged from 1.5 to 2 hours
in the presence of grape juice), resulting in lower
liver concentrations during first-pass and greater
hepatic extraction. This mechanism also seems plau-
sible, since phenacetin oral exposures increase
greater than dose-proportionally from 0.25 to 1g,[99]
suggesting that hepatic extraction may be saturated
at a 0.9g oral dose. Thus, based on these limited
Clin Pharmacokinet 2003; 42 (13)
1078
data, consumption of grape juice may modulate
CYP1A2 activity.
2.4 Cruciferous and Other Vegetables
Over 25 years ago, it was demonstrated that
cruciferous vegetables such as brussel sprouts, cab-
bage, broccoli and cauliflower increased CYP1A-
related activities in rat intestine and liver.[100,101]
Shortly thereafter, it was reported that the consump-
tion of a diet containing brussel sprouts and cabbage
for 7 days decreased the AUC of orally administered
phenacetin by an average of 49% in ten subjects.[102]
However, marked variability in the response was
observed, with phenacetin exposures reduced by
13–87% in six subjects, but unchanged in four sub-
jects. As a result, the dietary effect was not statisti-
cally significant. Subsequently, other investigators
demonstrated that consumption of a diet enriched
with broccoli for 10–12 days caused an approxi-
mately 12–19% (statistically significant) increase in
CYP1A2 activity, as assessed by caffeine urinary
metabolite ratios.[103,104] These modest, variable
CYP1A2-inducing effects may be due to glucosino-
late components in cruciferous vegetables, one of
which, glucobrassicin, has been demonstrated to
induce CYP1A2 expression and activity in rats.[105]
In addition to cruciferous vegetables, a recent
randomised crossover design study also examined
the effects of diets enriched with two other classes of
vegetables on CYP1A2, N-acetyltransferase 2 and
xanthine oxidase activities, as assessed by caffeine
urinary metabolite ratios.[106] Cruciferous vegetables
increased CYP1A2 activity by 18–37%, whereas the
diet supplemented with apiaceous vegetables (dill
weed, celery, parsley, parsnip, carrot) resulted in a
13–25% decrease in CYP1A2 activity. The investi-
gators speculated that furanocoumarins present in
the apiaceous vegetable diet were responsible for the
inhibitory effects on CYP1A2. As noted in section
2.2, some furanocoumarins present in grapefruit
juice have been demonstrated to inhibit CYP1A2 in
vitro.[92] Allium vegetables (chives, leeks, garlic,
onion) did not affect CYP1A2 activity, and none of
the test diets affected N-acetyltransferase 2 or xan-
thine oxidase activities.
© Adis Data Information BV 2003. All rights reserved.
Harris et al.
2.5 Cooked Meats
As recently reviewed,[107,108] the char-grilling,
frying or smoking of meats such as beef, fish or
chicken can generate multiple types of heterocyclic
aromatic amines (HA) and polycyclic aromatic hy-
drocarbons (PAH), the quantities of which vary with
the cooking method, temperature and duration.
These species have been demonstrated to induce
CYP1A1 and 1A2, which are thought to be key
enzymes involved in the activation of these potential
promutagenic and procarcinogenic species. Thus,
frequent consumption of char-grilled meats can po-
tentially increase both carcinogenic risk and, as de-
scribed below, the possibility of increased clearance
of drugs that are substrates of CYP1A2.
Over 25 years ago it was reported that the con-
sumption of a diet containing char-broiled beef for
4 days caused a marked decrease in phenacetin oral
bioavailability in nine subjects, with mean
Cmaxreduced by over 75%.[109] Phenacetin exposure
returned to baseline after the subjects were fed a
control diet. The increase in phenacetin metabolism
was attributed to the PAH content in the char-
broiled beef. In a subsequent study, 66 subjects
consumed two test diets containing beef that had
been fried at either a low or high temperature, the
latter of which produced markedly higher HA but
comparable PAH concentrations.[110] Consumption
of the high-temperature cooked beef for 7 days
resulted in a statistically significant (mean) 40%
increase in CYP1A2 activity, as measured by urin-
ary caffeine metabolite ratios, relative to CYP1A2
activity after consumption of the low-temperature
cooked beef. However, considerable interindividual
variability was observed, with 18 subjects display-
ing a decrease in CYP1A2 activity and 14 subjects
displaying approximately 2-fold or greater in-
creases. These data suggest that HA plays a princi-
ple role in the CYP1A2-inducing effects of fried
beef consumption and that these effects vary consid-
erably between individuals. Consistent with this ef-
fect, the consumption of a char-grilled beef diet was
demonstrated to induce intestinal CYP1A1 mRNA,
protein and activity, and to cause an approximately
2-fold increase in liver CYP1A2 activity as mea-
Clin Pharmacokinet 2003; 42 (13)
Dietary Effects on Drug Metabolism and Transport
sured by exhalation of 14CO2 following ingestion of
[3-methyl-14C] caffeine.[111]
Collectively, these studies have clearly demon-
strated that the consumption of test diets fortified
with char-grilled or high-temperature fried beef sig-
nificantly induces liver CYP1A2 activity. However,
it is possible that occasional consumption of such
foodstuff would have more modest effects on intra-
and interindividual variability in CYP1A2 activity.
Related studies, although beyond the scope of this
review, have investigated the enzymatic activation
of HA and PAH to carcinogenic derivatives,[112-114]
the effects of concomitant cruciferous vegetable
consumption,[115] and epidemiological evidence
linking HA and PAH intake and enzyme activities
with the risk of colorectal or other cancer.[116]
3. CYP2E1
As recently reviewed,[117] CYP2E1 was original-
ly identified and characterised as an ethanol-induci-
ble CYP in preclinical species and, in humans, is
expressed and inducible in the liver, kidney and
lung. Ethanol is a substrate of CYP2E1 and also
induces the enzyme via multiple mechanisms in-
cluding protein stabilisation, enhanced translational
efficiency and stimulation of gene transcription.
Other substrates of CYP2E1 include chlorzox-
azone,[118] which is commonly used as a probe of in
vivo activity, paracetamol,[119] tamoxifen[120] and
disulfiram.[121]
3.1 Ethanol
To assess the effect of long-term ethanol con-
sumption on CYP2E1 activity, the pharmaco-
kinetics of chlorzoxazone was characterised after
oral administration to 15 alcoholic (mean ethanol
intake 333 g/day) and 20 nonalcoholic (weekly in-
take <100 g) subjects.[122] On average, the oral clear-
ance of chlorzoxazone was 73% higher in al-
coholics. This was accompanied by a 2-fold higher
exposure to the primary CYP2E1-dependent metab-
olite, 6-hydroxychlorzoxazone. In a subsequent
study, alcoholics displayed an approximately 2-fold
higher oral clearance and 38% lower Cmax of
chlorzoxazone relative to nonalcoholics, but the
© Adis Data Information BV 2003. All rights reserved.
1079
same terminal-phase half-life.[123] These data sug-
gest that increased liver CYP2E1 activity in al-
coholics has a more marked effect on first-pass than
systemic chlorzoxazone elimination. In addition, it
was reported that an approximately 3-fold higher
rate of chlorzoxazone metabolism in alcoholics (rel-
ative to nonalcoholic controls) was essentially abol-
ished after 8 or more days of abstinence,[124] demon-
strating the rapidly reversible nature of CYP2E1
induction by ethanol.
CYP2E1 is capable of activating paracetamol to
its hepatotoxic metabolite, N-acetyl-p-benzoqui-
none amine, although CYP1A2 and 3A4 may also
contribute to the generation of this metabo-
lite.[125,126] As recently reviewed,[127-129] numerous
studies or case reports have assessed or described a
potential increased incidence of paracetamol-in-
duced hepatotoxicity in alcoholics relative to
nonalcoholics, but a correlation is not clear. In-
creased CYP2E1 levels from long-term ethanol con-
sumption would be expected to generate higher con-
centrations of the toxic metabolite. However, liver
glutathione S-transferase activity, which may be im-
paired in alcoholics who have liver disease, and
nutritional effects on hepatic glutathione levels are
also important factors, since the reactive metabolite
is detoxified via conjugation to glutathione. Further-
more, concomitantly ingested ethanol can competi-
tively inhibit CYP2E1-mediated formation of N-
acetyl-p-benzoquinone amine, thus counteracting an
increased rate of formation by ethanol-induced
CYP2E1. Therefore, the timing of ethanol and para-
cetamol administration can potentially influence the
nature and extent of the interaction.
In a recent study, the effects of acute ethanol
consumption on paracetamol metabolism in nonal-
coholic subjects were investigated.[130] Ethanol was
infused intravenously for 6 hours (with the resulting
exposure approximating that from consumption of a
750mL bottle of wine or a six-pack of beer) and, 8
hours after the end of the infusion, paracetamol was
administered orally. Thus, it was anticipated that
ethanol was eliminated from the body prior to para-
cetamol administration, thus avoiding a competitive
interaction. On average, ethanol administration was
Clin Pharmacokinet 2003; 42 (13)
1080
found to increase the formation of N-acetyl-p-
benzoquinone amine by 22% (range 2–38%), thus
suggesting a slight to moderate increase in
hepatotoxic risk. The investigators speculated that
this increase in CYP2E1 activity was primarily due
to protein stabilisation by ethanol.
3.2 Ethanol Disposition Affected by a Drug
The calcium channel antagonist verapamil is not
a CYP2E1 substrate, but is metabolised by
CYP3A4, CYP1A2 and enzymes of the CYP2C
subfamily.[131,132] In vitro, verapamil was found not
to inhibit CYP2E1 or alcohol dehydrogenase, al-
though its major metabolite, norverapamil, moder-
ately inhibited CYP2E1.[133] Single oral doses of
verapamil did not influence ethanol pharmaco-
kinetics or pharmacodynamics,[134,135] suggesting
that norverapamil concentrations from a single dose
of verapamil are insufficient to inhibit CYP2E1 in
vivo. In contrast, thrice daily administration for 5
days resulted in 17% and 30% increases in ethanol
Cmax and AUC, respectively, and prolongation of
ethanol pharmacodynamic effects.[136] The results of
this study provide an example of a diet-drug inter-
action in which the disposition of the diet compo-
nent is altered by the drug.
3.3 Watercress
The cutting or chewing of watercress results in
the hydrolysis of an isothiocyanate conjugate,
gluconasturtiin, and the liberation of high concentra-
tions of phenyl isothiocyanate, which is a potential
CYP2E1 inhibitor.[137] To assess the effect of water-
cress consumption on in vivo CYP2E1 activity, a
study was conducted in which ten healthy volunteers
ingested a single 50g serving 11 hours prior to
receiving chlorzoxazone.[138] On average, water-
cress consumption caused 28% and 56% increases
in Cmax and AUC, respectively. The timing of wa-
tercress consumption and chlorzoxazone adminis-
tration in this study suggests that the inhibitory
component in watercress was long-lived in the body
or that the interaction was not due to reversible
competitive inhibition of CYP2E1. In support of the
latter possibility, it was recently reported that phenyl
© Adis Data Information BV 2003. All rights reserved.
Harris et al.
isothiocyanate is a mechanism-based inactivator of
recombinantly expressed CYP2E1.[139] Regardless
of the mechanism, it appears that a single ingestion
of watercress may decrease the clearance of drugs
that are predominantly metabolised by CYP2E1.
3.4 Other Dietary Components and Fasting
Recently, stepwise multiple regression analyses
were performed to identify dietary and other factors
contributing to variability in CYP2E1 activity as
measured by oral chlorzoxazone clearance in 50
Japanese subjects living in Hawaii.[140] Bodyweight
accounted for 43% of the variability and, consistent
with the studies described below, correlated with
higher chlorzoxazone clearance. The consumption
of lettuce accounted for 7% of the variability and
also correlated with increased chlorzoxazone clear-
ance. Broccoli and black tea consumption each ac-
counted for 5–6% of the variability and correlated
with decreased enzyme activity. The association
between broccoli and reduced CYP2E1 activity is
consistent with an earlier report that broccoli con-
sumption for 12 days resulted in a 19% decrease in
CYP2E1 activity that was, however, not statistically
significant.[104]
Additionally, a number of studies have demon-
strated marked effects of fasting or dietary and body
composition on CYP2E1 activity. Oral chlorzox-
azone clearance was reduced by an average of 36%
in six healthy male volunteers after a 38-hour fast,
and was approximately 33% lower in normal-weight
women relative to obese women.[141] In addition,
obese nonalcoholic subjects displayed an approxi-
mately 2-fold higher mean oral clearance of
chlorzoxazone than normal-weight nonalcoholic
controls.[123] In a recent investigation,[142] 11 patients
(10 considered overweight) with abnormal liver
function tests probably related to fatty liver were
prescribed dietary sugar restriction. Six subjects
who were judged compliant with the diet demonstra-
ted significantly reduced body mass indices and an
average 20% decrease in oral chlorzoxazone clear-
ance at the end of a 2-month period. The noncomp-
liant subjects exhibited unchanged measurements.
Taken together, these studies demonstrate that fast-
Clin Pharmacokinet 2003; 42 (13)
Dietary Effects on Drug Metabolism and Transport
ing, carbohydrate intake, bodyweight and dietary
components may modulate CYP2E1 activity.
4. Phase II Enzymes
There are relatively few reports of metabolic
food-drug interactions involving phase II enzymes,
although some interactions have been described in-
volving uridine diphosphate glucuronosyltransfer-
ases (UGTs) and glutathione-S-transferases (GSTs).
UGTs are a superfamily of isozymes that catalyse
the conjugation of a glycosyl group from glucuronic
acid to numerous endo- and xenobiotics, generally
resulting in more polar and less toxic or reactive
metabolites.[143] Drugs that are directly glucuroni-
dated by UGTs include paracetamol, oxazepam, the
‘profen’ nonsteroidal anti-inflammatory agents,
morphine and other opioids.
GSTs are a superfamily of isozymes that catalyse
the conjugation of reduced glutathione to elec-
trophilic compounds and, in mammals, consists of
five subfamilies including GST-α, which appears to
be the predominant liver GST subfamily, GST-μ,
and GST-π.[144] Few drugs appear to be metabolised
primarily by direct glutathione conjugation, al-
though this pathway is thought to be important in
detoxification of the hepatotoxic paracetamol me-
tabolite and of environmental and occupational car-
cinogens.[144] As a result, the studies that have as-
sessed dietary effects on GST activity have been
primarily aimed at investigating mechanisms by
which specific dietary components may provide
protection against carcinogens.
4.1 Vegetables
In a controlled-diet study conducted in 10 sub-
jects, the consumption of brussel sprouts and cab-
bage for 10 days caused a 17% increase in the oral
clearance of paracetamol, accompanied by increased
plasma concentrations of glucuronide relative to
parent and increased urinary excretion of glucuroni-
de.[145] In the same study, the oral clearance of
oxazepam was increased to a similar extent, but
circulating plasma concentrations of glucuronide
relative to parent were unchanged. Recent reports
indicate that paracetamol and oxazepam
© Adis Data Information BV 2003. All rights reserved.
1081
glucuronidation are catalysed by UGT isoforms of
the 1A[146] and 2B[147] subfamilies respectively, al-
though the latter is the subject of debate.[148] In
addition, watercress consumption was reported to
increase the urinary excretion of two nicotine me-
tabolite glucuronides by 25–33%, suggesting that
phenyl isothiocyanate or another watercress compo-
nent is capable of inducing UGT isozymes in
vivo.[149] Thus, consumption of a diet rich in certain
vegetables may induce UGTs.
The effects of brussel sprout consumption on
specific GST isozymes has also been assessed. Diets
enriched with this vegetable were reported to cause
40–50% increases in plasma levels of GST-α,[150,151]
but not GST-π,[151] and 15–30% increases in rectal
levels of GST-α and GST-π.[152] The plasma GST-α
data are thought to reflect changes in hepatic levels
of this cytosolic isozyme as a result of hepatocyte
turnover and release into the systemic circulation. In
a recent work,[153] diets containing brassica (radish
sprouts, cauliflower, broccoli, cabbage) and allium
(chives, leeks, garlic, onion) vegetables caused up to
18% and 26% increases, respectively, in mean peri-
pheral lymphocyte GST-μ in women, but not men,
who express this polymorphic enzyme. Collectively,
these data and the paucity of drugs metabolised
primarily by GSTs suggest that dietary effects on
GST activity are unlikely to result in marked diet-
drug interactions. However, ongoing research may
elucidate important dietary effects on GST-medi-
ated detoxification of carcinogens.
5. Drug Transporters
Although drug transporters do not directly par-
ticipate in drug metabolism, they can play a major
role in drug disposition. In addition to mediating
drug excretion and absorption, transporters may al-
ter the extent of metabolism by affecting the dura-
tion of drug exposure at the site of metabolism. This
type of interplay has been proposed for the efflux
transporter P-glycoprotein and CYP3A4 in the en-
terocyte during drug absorption.[154] The following
reports illustrate food-drug interactions involving P-
glycoprotein and the organic anion transporting pol-
ypeptide (OATP) family of transporters.
Clin Pharmacokinet 2003; 42 (13)
1082
5.1 Fruit Juice
As described in section 1.1, it has been well
documented that grapefruit juice can affect the
pharmacokinetics of drugs that are metabolised by
CYP3A4. It has been suggested that grapefruit juice
can also affect the activity of P-glycoprotein,[155] and
that modulation of the activity of this transporter
may play a role in some of the observed drug inter-
actions involving CYP3A4 substrates.[46,155,156] Al-
though consumption of grapefruit juice does not
appear to affect the small bowel level of P-glycopro-
tein,[44] it may inhibit the activity of this transporter.
For example, coadministration of grapefruit juice
was shown to increase the rate of absorption but not
the overall exposure to digoxin,[157] a molecule
whose disposition is believed to be affected by both
renal and intestinal P-glycoprotein.[158,159] In addi-
tion, grapefruit juice has been shown to alter the
pharmacokinetics of cyclosporin, another drug
whose disposition is affected by P-glycoprotein.[50]
Interestingly, consumption of Seville orange juice,
which, like grapefruit juice, inhibits CYP3A4, did
not affect cyclosporin pharmacokinetics.[50] This re-
sult suggests that the component of grapefruit juice
that inhibits P-glycoprotein is not found in Seville
orange juice.
Recently, it was reported that grapefruit, orange
and apple juices decreased fexofenadine exposure
by 60–70% after oral administration.[160] The inves-
tigators also reported in vitro data demonstrating
that these juices inhibit OATP, but do not markedly
affect P-glycoprotein activity. Therefore, they con-
cluded that the mechanism of this interaction in-
volved inhibition of OATP transporters in the small
intestine, which are thought to mediate the uptake of
substrate drugs such as fexofenadine. Other drugs
that have been demonstrated to be substrates of
OATP transporters expressed predominantly in the
liver include digoxin[14] and pravastatin.[15]
5.2 St John’s Wort
As described in section 1.4, long-term consump-
tion of St John’s wort appears to induce CYP3A4.
Long-term consumption of this herbal dietary sup-
plement also appears to induce P-glycoprotein. Al-
© Adis Data Information BV 2003. All rights reserved.
Harris et al.
though a single dose of St John’s wort did not appear
to affect digoxin pharmacokinetics, 10 days of ther-
apy decreased digoxin exposure by approximately
25%.[161] The mechanism for this interaction prob-
ably involves induction of P-glycoprotein, since this
transporter is believed to be primarily responsible
for digoxin elimination.[16,162,163] Consistent with
this report, St John’s wort was shown to induce
duodenal P-glycoprotein and CYP3A4 expression
1.4- and 1.5-fold, respectively, in healthy human
volunteers.[164]
6. Effects of Dietary Macroconstituents
The influence of dietary macroconstituents (i.e.
total protein, fat and carbohydrate ratios and total
energy intake) on drug metabolism has been pre-
viously described in the literature. Briefly, chronic
low energy intake appears to lower the activity of
drug-metabolising enzyme systems whereas high
energy and protein intake appears to increase drug
metabolism.[3,165] For example, the clearances of
propranolol, aminopyrine and phenazone have been
shown to be significantly decreased by energy re-
duction.[3] Independent of energy intake, increased
protein intake appears to increase the activity of
hepatic drug-metabolising enzymes.[166,167] The ef-
fects of parenteral nutrition on these enzyme sys-
tems appear to be complex, depending on the com-
position of the nutrition, the health of the patient
prior to initiation of treatment, and the location
(hepatic versus intestinal) of the metabolic en-
zymes.[3,168-170] Unfortunately, the majority of re-
search on the effects of dietary macroconstituents
was performed prior to the last decade, and little
information is available on the specific drug-
metabolising enzymes that are affected. Further re-
search in this area may be of particular interest
today, given the popularity of various diets that
involving large modifications of dietary composi-
tion (e.g. Atkin’s and Ornish diets).
7. Concluding Remarks
A number of metabolic and transporter-related
food-drug interactions have been described, and are
summarised in table II. Some of these interactions,
Clin Pharmacokinet 2003; 42 (13)
Dietary Effects on Drug Metabolism and Transport 1083

Table II. Enzymes and transporters for which clinical diet-drug interactions have been reported
Enzyme or Dietary component Comment References
transporter
CYP3A4 Grapefruit juice Potent inhibitor. Cyclosporin, midazolam, terfenadine and felodipine AUC ↑ 34-43
by as much as 300%.
Seville orange juice Inhibitor. Felodipine AUC ↑ 76%. Other types of orange juice do not appear 48
to display effect
Red wine Modest inhibitor/inactivator. Felodipine AUC ↑ 15%. Cyclosporin AUC ↑ 59-61
13% or ↓30% depending on timing of administration
St John’s wort Potent inducer. Cyclosporin, indinavir and alprazolam AUC ↓ by up to 60% 64-68,70,71
Garlic Inducer based on single study. Saquinavir AUC ↓~50% 74
CYP1A2 Caffeine Modest inducer based on single study. Caffeine half-life ↑ 17% after 89
abstaining from heavy caffeine intake for 21 days
Grapefruit juice Potential inhibitor. Caffeine AUC ↑ 30%. Theophylline, caffeine, clozapine 91,93-95
oral pharmacokinetics ↔
Jufeng grape juice Potential activator. Phenacetin oral AUC ↓ 50% 96
Cruciferous Inducer. Phenacetin AUC ↓ 49%. Activity by caffeine urinary metabolite 102-104,106
vegetables ratios ↑~10–40%. Other vegetable types may also have an effect
Charbroiled meat Inducer. Phenacetin oral AUC ↓, Cmax ↓~75%. Caffeine breath test and 109-111
urinary metabolite ratios ↑~40%
CYP2E1 Ethanol Inducer. Chlorzoxazone AUC ~50% lower in alcoholics. Ethanol oral AUC ↑ 122,123,136
30% by verapamil
Watercress Inhibitor. Chlorzoxazone oral AUC ↑~50% 138
Phase II Enzymes Vegetables Potential, modest inducers of UGTs and GSTs. 145,150-153
Transporters Fruit juices P-glycoprotein inhibited by grapefruit but not orange juice. Cyclosporin AUC 50,160
↑~40%. Many juices potential inhibitors of OATP in gut. Fexofenadine AUC
↓ 60–70%
St John’s wort P-glycoprotein inducer. Digoxin AUC ↓ 25% 161
AUC = area under the plasma concentration-time curve; Cmax = maximum plasma concentration; CYP = cytochrome P450; GST =
glutathione S-transferase; OATP = organic anion transporting polypeptide; UGT = uridine diphosphate glucuronosyltransferase; ↔ =
unchanged; ↑ = increased; ↓ = decreased.

such as the effects of grapefruit juice, red wine and
St John’s wort on the disposition of orally adminis-
tered drugs that are CYP3A4 or P-glycoprotein sub-
strates, appear to be clinically important, potentially
necessitating dosage adjustments. In general, diet-
drug interactions involving CYP1A2, CYP2E1,
UGTs and GSTs appear to be smaller and may be
less clinically important. Because diets are so di-
verse and complex, it can be very difficult to assess
the frequency and clinical relevance of these interac-
tions. Moreover, it should be noted that the magni-
tude of diet-drug interactions may vary across indi-
viduals because of interindividual variability in
enzyme activities.
Consumption of foods that contain complex mix-
tures of phytochemicals, such as herbs, spices, teas,
fruits and vegetables, clearly has the potential to
affect drug-metabolising enzymes and transporter
systems. Indeed, in vitro and preclinical data in rats
suggest that a variety of foodstuffs, including herbal
teas (dandelion, peppermint), various component
fruits, vegetables and herbs, and fish oil, can modu-
late the activity of drug-metabolising sys-
tems.[171-175] It is not yet known whether these ef-
fects are predictive of what will be observed clini-
cally.
The regular ingestion of herbal dietary supple-
ments may deliver large numbers and quantities of
compounds with the potential to modulate drug-
metabolising enzyme or transporter activity, making
these dietary factors of particular concern. Because
they are not regulated like drugs, their compositions,
doses and frequencies of use may be more variable,
further adding to the complexity of predicting their
effects on drug disposition. The St John’s wort
reports described above are the first significant ex-

© Adis Data Information BV 2003. All rights reserved. Clin Pharmacokinet 2003; 42 (13)
1084
amples of metabolic herbal supplement-drug inter-
actions. Additional research on the potential of other
popular herbal supplements to provoke diet-drug
interactions appears warranted.
In conclusion, dietary constituents can be impor-
tant contributors to inter- and intra-individual vari-
ability in drug metabolism and pharmacokinetics. In
addition to the significant amount of research being
performed to elucidate genetic determinants of this
variability, more research is needed to elucidate
environmental determinants, including diet. This
type of research may ultimately lead to more effica-
cious therapy and a reduction in the incidence of
drug-induced adverse events.
Acknowledgements
The authors have provided no information on sources of
funding or on conflicts of interest directly relevant to the
content of this study.
References
1. Singh BN. Effects of food on clinical pharmacokinetics. Clin
Pharmacokinet 1999; 37 (3): 213-55
2. US Food and Drug Administration. Guidance for industry.
Food-effect bioavailability and fed bioequivalence studies.
Rockville, MD: Food and Drug Administration, 2002.
3. Walter-Sack I, Klotz U. Influence of diet and nutritional status
on drug metabolism. Clin Pharmacokinet 1996; 31 (1): 47-64
4. Rowland M, Tozer TN. Clinical pharmacokinetics: concepts
and applications. 3rd ed. Media (PA): Williams & Wilkins,
1995
5. Conney AH, Buening MK, Pantuck EJ, et al. Regulation of
human drug metabolism by dietary factors. Ciba Found Symp
1980; 76: 147-67
6. Tsunoda SM, Velez RL, von Moltke LL, et al. Differentiation
of intestinal and hepatic cytochrome P450 3A activity with use
of midazolam as an in vivo probe: effect of ketoconazole. Clin
Pharmacol Ther 1999; 66 (5): 461-71
7. Varhe A, Olkkola KT, Neuvonen PJ. Oral triazolam is potential-
ly hazardous to patients receiving systemic antimycotics keto-
conazole or itraconazole. Clin Pharmacol Ther 1994; 56 (6 Pt
1): 601-7
8. Kivisto KT, Kantola T, Neuvonen PJ. Different effects of itra-
conazole on the pharmacokinetics of fluvastatin and lovastatin.
Br J Clin Pharmacol 1998; 46 (1): 49-53
9. Honig PK, Wortham DC, Zamani K, et al. Terfenadine-ketoco-
nazole interaction: pharmacokinetic and electrocardiographic
consequences [published erratum appears in JAMA 1993; 269:
2088]. JAMA 1993; 269 (12): 1513-8
10. Raschetti R, Morgutti M, Menniti-Ippolito F, et al. Suspected
adverse drug events requiring emergency department visits or
hospital admissions. Eur J Clin Pharmacol 1999; 54 (12):
959-63
© Adis Data Information BV 2003. All rights reserved.
Harris et al.
11. Szoka PR, Edgren RA. Drug interactions with oral contracep-
tives: compilation and analysis of an adverse experience report
database. Fertil Steril 1988; 49 (5 Suppl. 2): 31S-8S
12. Smith DA, Abel SM, Hyland R, et al. Human cytochrome
P450s: selectivity and measurement in vivo. Xenobiotica
1998; 28 (12): 1095-128
13. Flockhart DA. Cytochrome P450 drug interaction table [online].
Available from URL: http://medicine.iupui.edu/flockhart/
[Accessed 2003 Aug 4]
14. Kullak-Ublick GA, Ismair MG, Stieger B, et al. Organic anion-
transporting polypeptide B (OATP-B) and its functional com-
parison with three other OATPs of human liver. Gastroenterol-
ogy 2001; 120: 525-33
15. Hsiang B, Zhu Y, Wang Z, et al. A novel human hepatic organic
anion transporting polypeptide (OATP2): identification of a
liver-specific human organic anion transporting polypeptide
and identification of rat and human hydroxymethylglutaryl-
CoA reductase inhibitor transporters. J Biol Chem 1999; 274:
37161-8
16. Tanigawara Y. Role of P-glycoprotein in drug disposition. Ther
Drug Monit 2000; 22 (1): 137-40
17. Miners JO, Mackenzie PI. Drug glucuronidation in humans.
Pharmacol Ther 1991; 51 (3): 347-69
18. Cvetkovic M, Leake B, Fromm MF, et al. OATP and P-
glycoprotein transporters mediate the cellular uptake and ex-
cretion of fexofenadine. Drug Metab Dispos 1999; 27: 866-71
19. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharma-
codynamic consequences and clinical relevance of cytochrome
P450 3A4 inhibition. Clin Pharmacokinet 2000; 38 (1): 41-57
20. Guengerich FP. Cytochrome P-450 3A4: regulation and role in
drug metabolism. Annu Rev Pharmacol Toxicol 1999; 39:
1-17
21. Hall SD, Thummel KE, Watkins PB, et al. Molecular and
physical mechanisms of first-pass extraction. Drug Metab
Dispos 1999; 27 (2): 161-6
22. Kolars JC, Lown KS, Schmiedlin-Ren P, et al. CYP3A gene
expression in human gut epithelium. Pharmacogenetics 1994;
4 (5): 247-59
23. Watkins PB. Drug metabolism by cytochromes P450 in the liver
and small bowel. Gastroenterol Clin North Am 1992; 21 (3):
511-26
24. Gorski JC, Jones DR, Haehner-Daniels BD, et al. The contribu-
tion of intestinal and hepatic CYP3A to the interaction be-
tween midazolam and clarithromycin. Clin Pharmacol Ther
1998; 64 (2): 133-43
25. Honig PK, Wortham DC, Zamani K, et al. Terfenadine-ketoco-
nazole interaction: pharmacokinetic and electrocardiographic
consequences. JAMA 1993; 269: 1513-8
26. Back DJ, Bates M, Bowden A, et al. The interaction of
phenobarbital and other anticonvulsants with oral contracep-
tive steroid therapy. Contraception 1980; 22 (5): 495-503
27. Offermann G, Keller F, Molzahn M. Low cyclosporin A blood
levels and acute graft rejection in a renal transplant recipient
during rifampin treatment. Am J Nephrol 1985; 5: 385-7
28. Tang W, Stearns RA. Heterotropic cooperativity of cytochrome
P450 3A4 and potential drug-drug interactions. Curr Drug
Metab 2001; 2 (2): 185-98
29. Shou M, Lin Y, Lu P, et al. Enzyme kinetics of cytochrome
P450-mediated reactions. Curr Drug Metab 2001; 2 (1): 17-36
30. Schrag ML, Wienkers LC. Covalent alteration of the CYP3A4
active site: evidence for multiple substrate binding domains.
Arch Biochem Biophys 2001; 391 (1): 49-55
Clin Pharmacokinet 2003; 42 (13)
Dietary Effects on Drug Metabolism and Transport
31. Ameer B, Weintraub RA. Drug interactions with grapefruit
juice. Clin Pharmacokinet 1997; 33 (2): 103-21
32. Bailey DG, Malcolm J, Arnold O, et al. Grapefruit juice-drug
interactions. Br J Clin Pharmacol 1998; 46 (2): 101-10
33. Fuhr U. Drug interactions with grapefruit juice: extent, probable
mechanism and clinical relevance. Drug Saf 1998; 18 (4):
251-72
34. Ku YM, Min DI, Flanigan M. Effect of grapefruit juice on the
pharmacokinetics of microemulsion cyclosporine and its me-
tabolite in healthy volunteers: does the formulation difference
matter? J Clin Pharmacol 1998; 38 (10): 959-65
35. Min DI, Ku YM, Perry PJ, et al. Effect of grapefruit juice on
cyclosporine pharmacokinetics in renal transplant patients.
Transplantation 1996; 62 (1): 123-5
36. Proppe DG, Hoch OD, McLean AJ, et al. Influence of chronic
ingestion of grapefruit juice on steady-state blood concentra-
tions of cyclosporine A in renal transplant patients with stable
graft function. Br J Clin Pharmacol 1995; 39 (3): 337-8
37. Benton RE, Honig PK, Zamani K, et al. Grapefruit juice alters
terfenadine pharmacokinetics, resulting in prolongation of re-
polarization on the electrocardiogram. Clin Pharmacol Ther
1996; 59 (4): 383-8
38. Clifford CP, Adams DA, Murray S, et al. The cardiac effects of
terfenadine after inhibition of its metabolism by grapefruit
juice. Eur J Clin Pharmacol 1997; 52 (4): 311-5
39. Honig PK, Wortham DC, Lazarev A, et al. Grapefruit juice
alters the systemic bioavailability and cardiac repolarization of
terfenadine in poor metabolizers of terfenadine. J Clin
Pharmacol 1996; 36 (4): 345-51
40. Goho C. Oral midazolam-grapefruit juice drug interaction.
Pediatr Dent 2001; 23 (4): 365-6
41. Kupferschmidt HH, Ha HR, Ziegler WH, et al. Interaction
between grapefruit juice and midazolam in humans. Clin
Pharmacol Ther 1995; 58 (1): 20-8
42. Bailey DG, Arnold JM, Bend JR, et al. Grapefruit juice-
felodipine interaction: reproducibility and characterization
with the extended release drug formulation. Br J Clin
Pharmacol 1995; 40 (2): 135-40
43. Edgar B, Bailey D, Bergstrand R, et al. Acute effects of
drinking grapefruit juice on the pharmacokinetics and dynam-
ics of felodipine: and its potential clinical relevance. Eur J Clin
Pharmacol 1992; 42 (3): 313-7
44. Lown KS, Bailey DG, Fontana RJ, et al. Grapefruit juice
increases felodipine oral availability in humans by decreasing
intestinal CYP3A protein expression. J Clin Invest 1997; 99
(10): 2545-53
45. Feldman EB. How grapefruit juice potentiates drug bioavailabil-
ity. Nutr Rev 1997; 55 (11 Pt 1): 398-400
46. Kane GC, Lipsky JJ. Drug-grapefruit juice interactions. Mayo
Clin Proc 2000; 75 (9): 933-42
47. Lilja JJ, Kivisto KT, Backman JT, et al. Effect of grapefruit
juice dose on grapefruit juice-triazolam interaction: repeated
consumption prolongs triazolam half-life. Eur J Clin
Pharmacol 2000 Aug; 56 (5): 411-5
48. Malhotra S, Bailey DG, Paine MF, et al. Seville orange juice-
felodipine interaction: comparison with dilute grapefruit juice
and involvement of furocoumarins. Clin Pharmacol Ther 2001;
69 (1): 14-23
49. Backman JT, Maenpaa J, Belle DJ, et al. Lack of correlation
between in vitro and in vivo studies on the effects of tangeretin
and tangerine juice on midazolam hydroxylation. Clin
Pharmacol Ther 2000; 67 (4): 382-90
© Adis Data Information BV 2003. All rights reserved.
1085
50. Edwards DJ, Fitzsimmons ME, Schuetz EG, et al. 6′,7′-
Dihydroxybergamottin in grapefruit juice and Seville orange
juice: effects on cyclosporine disposition, enterocyte CYP3A4,
and P-glycoprotein. Clin Pharmacol Ther 1999; 65 (3): 237-44
51. Wollin SD, Jones PJ. Alcohol, red wine and cardiovascular
disease. J Nutr 2001; 131 (5): 1401-4
52. Mukamal KJ, Maclure M, Muller JE, et al. Prior alcohol
consumption and mortality following acute myocardial infarc-
tion. JAMA 2001; 285 (15): 1965-70
53. de Lorimier AA. Alcohol, wine, and health. Am J Surg 2000;
180 (5): 357-61
54. Renaud S, Gueguen R. The French paradox and wine drinking.
Novartis Found Symp 1998; 216: 208-17
55. Chan WK, Nguyen LT, Miller VP, et al. Mechanism-based
inactivation of human cytochrome P450 3A4 by grapefruit
juice and red wine. Life Sci 1998; 62 (10): L135-42
56. Chang TK, Yeung RK. Effect of trans-resveratrol on
7-benzyloxy-4-trifluoromethylcoumarin O-dealkylation cata-
lyzed by human recombinant CYP3A4 and CYP3A5. Can J
Physiol Pharmacol 2001; 79 (3): 220-6
57. Chan WK, Delucchi AB. Resveratrol, a red wine constituent, is
a mechanism-based inactivator of cytochrome P450 3A4. Life
Sci 2000; 67 (25): 3103-12
58. Piver B, Berthou F, Dreano Y, et al. Inhibition of CYP3A,
CYP1A and CYP2E1 activities by resveratrol and other non
volatile red wine components. Toxicol Lett 2001; 125 (1-3):
83-91
59. Tsunoda SM, Harris RZ, Christians U, et al. Red wine decreases
cyclosporine bioavailability. Clin Pharmacol Ther 2001; 70
(5): 462-7
60. Tsunoda SM, Harris RZ, Freeman RB, et al. Acute and chronic
wine effects on cyclosporine (CYA) disposition. Br J Clin
Pharmacol 2000, 42
61. Offman EM, Freeman DJ, Dresser GK, et al. Red wine-
cisapride interaction: comparison with grapefruit juice. Clin
Pharmacol Ther 2001; 70 (1): 17-23
62. Nelson L, Perrone J. Herbal and alternative medicine. Emerg
Med Clin North Am 2000; 18 (4): 709-22
63. Izzo AA, Ernst E. Interactions between herbal medicines and
prescribed drugs: a systematic review. Drugs 2001; 61 (15):
2163-75
64. Barone GW, Gurley BJ, Ketel BL, et al. Drug interaction
between St John’s wort and cyclosporine. Ann Pharmacother
2000; 34 (9): 1013-6
65. Ruschitzka F, Meier PJ, Turina M, et al. Acute heart transplant
rejection due to Saint John’s wort. Lancet 2000; 355 (9203):
548-9
66. Karliova M, Treichel U, Malago M, et al. Interaction of
Hypericum perforatum (St John’s wort) with cyclosporin A
metabolism in a patient after liver transplantation. J Hepatol
2000; 33 (5): 853-5
67. Breidenbach T, Kliem V, Burg M, et al. Profound drop of
cyclosporin A whole blood trough levels caused by St John’s
wort (Hypericum perforatum). Transplantation 2000; 69 (10):
2229-30
68. Piscitelli SC, Burstein AH, Chaitt D, et al. Indinavir concentra-
tions and St John’s wort [published erratum appears in Lancet
2001; 357: 1210]. Lancet 2000; 355 (9203): 547-8
69. Gorski JC, Hamman MA, Wang Z, et al. The effect of St John’s
wort on the efficacy of oral contraception [abstract]. Clin
Pharmacol Ther 2002; 71 (2): P25
70. Markowitz JS, DeVane CL, Boulton DW, et al. Effect of St
John’s wort (Hypericum perforatum) on cytochrome P-450
Clin Pharmacokinet 2003; 42 (13)
1086
2D6 and 3A4 activity in healthy volunteers. Life Sci 2000; 66
(9): L133-9
71. Wang Z, Gorski JC, Hamman MA, et al. The effects of St
John’s wort (Hypericum perforatum) on human cytochrome
P450 activity. Clin Pharmacol Ther 2001; 70 (4): 317-26
72. Moore LB, Goodwin B, Jones SA, et al. St John’s wort induces
hepatic drug metabolism through activation of the pregnane X
receptor. Proc Natl Acad Sci U S A 2000; 97 (13): 7500-2
73. Foster BC, Foster MS, Vandenhoek S, et al. An in vitro
evaluation of human cytochrome P450 3A4 and P-glycopro-
tein inhibition by garlic. J Pharm Pharm Sci 2001; 4 (2): 176-
84
74. Piscitelli SC, Burstein AH, Welden N, et al. The effect of garlic
supplements on the pharmacokinetics of saquinavir. Clin
Infect Dis 2002; 34 (2): 234-8
75. Ahsan CH, Renwick AG, Waller DG, et al. The influence of
dose and ethnic origins on the pharmacokinetics of nifedipine.
Clin Pharmacol Ther 1993; 54 (3): 329-38
76. Rashid TJ, Martin U, Clarke H, et al. Factors affecting the
absolute bioavailability of nifedipine. Br J Clin Pharmacol
1995; 40 (1): 51-8
77. Yu KS, Cho JY, Shon JH, et al. Ethnic differences and relation-
ships in the oral pharmacokinetics of nifedipine and erythro-
mycin. Clin Pharmacol Ther 2001; 70 (3): 228-36
78. Kinirons MT, Lang CC, He HB, et al. Triazolam pharmaco-
kinetics and pharmacodynamics in Caucasians and Southern
Asians: ethnicity and CYP3A activity. Br J Clin Pharmacol
1996; 41 (1): 69-72
79. Ahsan CH, Renwick AG, Macklin B, et al. Ethnic differences in
the pharmacokinetics of oral nifedipine. Br J Clin Pharmacol
1991; 31 (4): 399-403
80. Stein CM, Sadeque AJ, Murray JJ, et al. Cyclosporine
pharmacokinetics and pharmacodynamics in African Ameri-
can and white subjects. Clin Pharmacol Ther 2001; 69 (5):
317-23
81. Wandel C, Witte JS, Hall JM, et al. CYP3A activity in African
American and European American men: population differ-
ences and functional effect of the CYP3A4*1B 5′-promoter
region polymorphism. Clin Pharmacol Ther 2000; 68 (1): 82-
91
82. Castaneda-Hernandez G, Palma-Aguirre JA, Montoya-Cabrera
MA, et al. Interethnic variability in nifedipine disposition:
reduced systemic plasma clearance in Mexican subjects. Br J
Clin Pharmacol 1996; 41 (5): 433-4
83. Palma-Aguirre JA, Gonzalez-Llaven J, Flores-Murrieta FJ, et al.
Bioavailability of oral cyclosporine in healthy Mexican volun-
teers: evidence for interethnic variability. J Clin Pharmacol
1997; 37 (7): 630-4
84. Miners JO, McKinnon RA. CYP1A. In: Levy RH, Thummel
KE, Trager WF, et al., editors. Metabolic drug interactions.
Philadelphia: Lippincott Williams & Wilkins, 2000: 61-73
85. Jang GR, Maurel JP. Rifampin, dexamethasone, and
omeprazole. In: Levy RH, Thummel KE, Trager WF, et al.,
editors. Metabolic drug interactions. Philadelphia (PA): Lip-
pincott Williams & Wilkins, 2000: 691-706
86. Ayalogu EO, Snelling J, Lewis DF, et al. Induction of hepatic
CYP1A2 by the oral administration of caffeine to rats: lack of
association with the Ah locus. Biochim Biophys Acta 1995;
1272 (2): 89-94
87. Chen L, Bondoc FY, Lee MJ, et al. Caffeine induces cyto-
chrome P4501A2: induction of CYP1A2 by tea in rats. Drug
Metab Dispos 1996; 24 (5): 529-33
© Adis Data Information BV 2003. All rights reserved.
Harris et al.
88. Goasduff T, Dreano Y, Guillois B, et al. Induction of liver and
kidney CYP1A1/1A2 by caffeine in rat. Biochem Pharmacol
1996; 52 (12): 1915-9
89. Caraco Y, Zylber-Katz E, Granit L, et al. Does restriction of
caffeine intake affect mixed function oxidase activity and
caffeine metabolism? Biopharm Drug Dispos 1990; 11 (7):
639-43
90. Fuhr U, Kummert AL. The fate of naringin in humans: a key to
grapefruit juice-drug interactions? Clin Pharmacol Ther 1995;
58 (4): 365-73
91. Fuhr U, Klittich K, Staib AH. Inhibitory effect of grapefruit
juice and its bitter principal, naringenin, on CYP1A2 depen-
dent metabolism of caffeine in man. Br J Clin Pharmacol 1993;
35 (4): 431-6
92. Tassaneeyakul W, Guo LQ, Fukuda K, et al. Inhibition selectiv-
ity of grapefruit juice components on human cytochromes
P450. Arch Biochem Biophys 2000; 378 (2): 356-63
93. Fuhr U, Maier A, Keller A, et al. Lacking effect of grapefruit
juice on theophylline pharmacokinetics. Int J Clin Pharmacol
Ther 1995; 33 (6): 311-4
94. Maish WA, Hampton EM, Whitsett TL, et al. Influence of
grapefruit juice on caffeine pharmacokinetics and pharmaco-
dynamics. Pharmacotherapy 1996; 16 (6): 1046-52
95. Lane HY, Jann MW, Chang YC, et al. Repeated ingestion of
grapefruit juice does not alter clozapine’s steady-state plasma
levels, effectiveness, and tolerability. J Clin Psychiatry 2001;
62 (10): 812-7
96. Xiao DS, Zhi PZ, Zhong XW, et al. Possible enhancement of
the first-pass metabolism of phenacetin by ingestion of grape
juice in Chinese subjects. Br J Clin Pharmacol 1999; 48 (4):
638-40
97. Buening MK, Chang RL, Huang MT, et al. Activation and
inhibition of benzo(a)pyrene and aflatoxin B1 metabolism in
human liver microsomes by naturally occurring flavonoids.
Cancer Res 1981; 41 (1): 67-72
98. Ekins S, Ring BJ, Binkley SN, et al. Autoactivation and
activation of the cytochrome P450s. Int J Clin Pharmacol Ther
1998; 36 (12): 642-51
99. Raaflaub J, Dubach UC. On the pharmacokinetics of phenacetin
in man. Eur J Clin Pharmacol 1975; 8 (3-4): 261-5
100. Loub WD, Wattenberg LW, Davis DW. Aryl hydrocarbon
hydroxylase induction in rat tissues by naturally occurring
indoles of cruciferous plants. J Natl Cancer Inst 1975; 54 (4):
985-8
101. Pantuck EJ, Hsiao KC, Loub WD, et al. Stimulatory effect of
vegetables on intestinal drug metabolism in the rat. J
Pharmacol Exp Ther 1976; 198 (2): 278-83
102. Pantuck EJ, Pantuck CB, Garland WA, et al. Stimulatory effect
of brussels sprouts and cabbage on human drug metabolism.
Clin Pharmacol Ther 1979; 25 (1): 88-95
103. Vistisen K, Poulsen HE, Loft S. Foreign compound metabolism
capacity in man measured from metabolites of dietary caffeine.
Carcinogenesis 1992; 13 (9): 1561-8
104. Kall MA, Vang O, Clausen J. Effects of dietary broccoli on
human in vivo drug metabolizing enzymes: evaluation of
caffeine, oestrone and chlorzoxazone metabolism. Carcino-
genesis 1996; 17 (4): 793-9
105. Bonnesen C, Stephensen PU, Andersen O, et al. Modulation of
cytochrome P-450 and glutathione S-transferase isoform ex-
pression in vivo by intact and degraded indolyl glucosinolates.
Nutr Cancer 1999; 33 (2): 178-87
106. Lampe JW, King IB, Li S, et al. Brassica vegetables increase
and apiaceous vegetables decrease cytochrome P450 1A2 ac-
Clin Pharmacokinet 2003; 42 (13)
Dietary Effects on Drug Metabolism and Transport
tivity in humans: changes in caffeine metabolite ratios in
response to controlled vegetable diets. Carcinogenesis 2000;
21 (6): 1157-62
107. Knize MG, Salmon CP, Pais P, et al. Food heating and the
formation of heterocyclic aromatic amine and polycyclic aro-
matic hydrocarbon mutagens/carcinogens. Adv Exp Med Biol
1999; 459: 179-93
108. Sugimura T. Nutrition and dietary carcinogens. Carcinogenesis
2000; 21 (3): 387-95
109. Conney AH, Pantuck EJ, Hsiao KC, et al. Enhanced phenacetin
metabolism in human subjects fed charcoal-broiled beef. Clin
Pharmacol Ther 1976; 20 (6): 633-42
110. Sinha R, Rothman N, Brown ED, et al. Pan-fried meat contain-
ing high levels of heterocyclic aromatic amines but low levels
of polycyclic aromatic hydrocarbons induces cytochrome
P4501A2 activity in humans. Cancer Res 1994; 54 (23): 6154-
9 analogues and protective approaches. Crit Rev Toxicol 2001;
111. Fontana RJ, Lown KS, Paine MF, et al. Effects of a chargrilled
meat diet on expression of CYP3A, CYP1A, and P-glycoprote-
in levels in healthy volunteers. Gastroenterology 1999; 117
(1): 89-98
112. Turesky RJ, Lang NP, Butler MA, et al. Metabolic activation of
carcinogenic heterocyclic aromatic amines by human liver and
colon. Carcinogenesis 1991; 12 (10): 1839-45
113. Hein DW, Doll MA, Rustan TD, et al. Metabolic activation and
deactivation of arylamine carcinogens by recombinant human
NAT1 and polymorphic NAT2 acetyltransferases. Carcino-
genesis 1993; 14 (8): 1633-8
114. Boobis AR, Lynch AM, Murray S, et al. CYP1A2-catalyzed
conversion of dietary heterocyclic amines to their proximate
carcinogens is their major route of metabolism in humans.
Cancer Res 1994; 54 (1): 89-94
115. Steinkellner H, Rabot S, Freywald C, et al. Effects of crucifer-
ous vegetables and their constituents on drug metabolizing
enzymes involved in the bioactivation of DNA-reactive dietary
carcinogens. Mutat Res 2001; 480 (SI): 285-97
116. Le Marchand L, Hankin JH, Wilkens LR, et al. Combined
effects of well-done red meat, smoking, and rapid N-Acetyl-
transferase 2 and CYP1A2 phenotypes in increasing colorectal
cancer risk. Cancer Epidemiol Biomarkers Prev 2001; 10 (12):
1259-66
117. Raucy J, Carpenter SP. CYP2E1. In: Levy RH, Thummel KE,
Trager WF, et al., editors. Metabolic drug interactions. Phila-
delphia (PA): Lippincott Williams & Wilkins, 2000: 95-114
118. Peter R, Bocker R, Beaune PH, et al. Hydroxylation of
chlorzoxazone as a specific probe for human liver cytochrome
P-450IIE1. Chem Res Toxicol 1990; 3: 566-73
119. Raucy JL, Lasker JM, Lieber CS, et al. Acetaminophen activa-
tion by human liver cytochromes P450IIE1 and P450IA2.
Arch Biochem Biophys 1989; 271: 270-83
120. Styles JA, Davies A, Lim CK, et al. Genotoxicity of tamoxifen,
tamoxifen epoxide and toremifene in human lymphoblastoid
cells containing human cytochrome P450s. Carcinogenesis
1994; 15: 5-9
121. Guengerich FP, Kim DH, Iwasaki M. Role of human cyto-
chrome P-450 IIE1 in the oxidation of many low molecular
weight cancer suspects. Chem Res Toxicol 1991; 4: 168-79
122. Girre C, Lucas D, Hispard E, et al. Assessment of cytochrome
P4502E1 induction in alcoholic patients by chlorzoxazone
pharmacokinetics. Biochem Pharmacol 1994; 47 (9): 1503-8
123. de la Maza MP, Hirsch S, Petermann M, et al. Changes in
microsomal activity in alcoholism and obesity. Alcohol Clin
Exp Res 2000; 24 (5): 605-10
© Adis Data Information BV 2003. All rights reserved.
1087
124. Lucas D, Menez C, Girre C, et al. Decrease in cytochrome
P4502E1 as assessed by the rate of chlorzoxazone hydroxyl-
ation in alcoholics during the withdrawal phase. Alcohol Clin
Exp Res 1995; 19 (2): 362-6
125. Zaher H, Buters JT, Ward JM, et al. Protection against aceta-
minophen toxicity in CYP1A2 and CYP2E1 double-null mice.
Toxicol Appl Pharmacol 1998; 152 (1): 193-9
126. Sinclair J, Jeffery E, Wrighton S, et al. Alcohol-mediated
increases in acetaminophen hepatotoxicity: role of CYP2E and
CYP3A. Biochem Pharmacol 1998; 55 (10): 1557-65
127. McClain CJ, Price S, Barve S, et al. Acetaminophen hepato-
toxicity: an update. Curr Gastroenterol Rep 1999; 1 (1): 42-9
128. Prescott LF. Paracetamol, alcohol and the liver. Br J Clin
Pharmacol 2000; 49 (4): 291-301
129. Bessems JG, Vermeulen NP. Paracetamol (acetaminophen)-
induced toxicity: molecular and biochemical mechanisms,
31 (1): 55-138
130. Thummel KE, Slattery JT, Ro H, et al. Ethanol and production
of the hepatotoxic metabolite of acetaminophen in healthy
adults. Clin Pharmacol Ther 2000; 67 (6): 591-9
131. Kroemer HK, Gautier JC, Beaune P, et al. Identification of
P450 enzymes involved in metabolism of verapamil in
humans. Naunyn Schmiedebergs Arch Pharmacol 1993; 348
(3): 332-7
132. Busse D, Cosme J, Beaune P, et al. Cytochromes of the P450
2C subfamily are the major enzymes involved in the O-
demethylation of verapamil in humans. Naunyn Sch-
miedebergs Arch Pharmacol 1995; 353 (1): 116-21
133. Ammon E, Klotz U. In-vitro assessment of a possible verapamil/
ethanol interaction [abstract]. Naunyn Schmiedebergs Arch
Pharmacol 1997; 355: (R123)
134. Zacny JP, Yajnik S. Effects of calcium channel inhibitors on
ethanol effects and pharmacokinetics in healthy volunteers.
Alcohol 1993; 10 (6): 505-9
135. Perez-Reyes M, White WR, Hicks RE. Interaction between
ethanol and calcium channel blockers in humans. Alcohol Clin
Exp Res 1992; 16 (4): 769-75
136. Bauer LA, Schumock G, Horn J, et al. Verapamil inhibits
ethanol elimination and prolongs the perception of intoxica-
tion. Clin Pharmacol Ther 1992; 52 (1): 6-10
137. Hecht SS. Inhibition of carcinogenesis by isothiocyanates. Drug
Metab Rev 2000; 32 (3-4): 395-411
138. Leclercq I, Desager JP, Horsmans Y. Inhibition of chlorzox-
azone metabolism, a clinical probe for CYP2E1, by a single
ingestion of watercress. Clin Pharmacol Ther 1998; 64 (2):
144-9
139. Nakajima M, Yoshida R, Shimada N, et al. Inhibition and
inactivation of human cytochrome P450 isoforms by phenethyl
isothiocyanate. Drug Metab Dispos 2001; 29 (8): 1110-3
140. Marchand LL, Wilkinson GR, Wilkens LR. Genetic and dietary
predictors of CYP2E1 activity: a phenotyping study in Hawaii
Japanese using chlorzoxazone. Cancer Epidemiol Biomarkers
Prev 1999; 8 (6): 495-500
141. O’Shea D, Davis SN, Kim RB, et al. Effect of fasting and
obesity in humans on the 6-hydroxylation of chlorzoxazone: a
putative probe of CYP2E1 activity. Clin Pharmacol Ther 1994;
56 (4): 359-67
142. Leclercq I, Horsmans Y, Desager JP, et al. Dietary restriction of
energy and sugar results in a reduction in human cytochrome
P450 2E1 activity. Br J Nutr 1999; 82 (4): 257-62
143. Tephly TR, Green MD. UDP-glucuronosyltransferases. In:
Levy RH, Thummel KE, Trager WF, et al., editors. Metabolic
Clin Pharmacokinet 2003; 42 (13)
1088
drug interactions. Philadelphia (PA): Lippincott Williams &
Wilkins, 2000: 161-74
144. Eaton DL, Bammler TK. Glutathione S-transferases. In: Levy
RH, Thummel KE, Trager WF, et al., editors. Metabolic drug
interactions. Philadelphia (PA): Lippincott Williams & Wil-
kins, 2000: 175-90
145. Pantuck EJ, Pantuck CB, Anderson KE, et al. Effect of brussels
sprouts and cabbage on drug conjugation. Clin Pharmacol Ther
1984; 35 (2): 161-9
146. Court MH, Duan SX, von Moltke LL, et al. Interindividual
variability in acetaminophen glucuronidation by human liver
microsomes: identification of relevant acetaminophen UDP-
glucuronosyltransferase isoforms. J Pharmacol Exp Ther
2001; 299 (3): 998-1006
147. Patel M, Tang BK, Kalow W. (S)-Oxazepam glucuronidation is
inhibited by ketoprofen and other substrates of UGT2B7.
Pharmacogenetics 1995; 5 (1): 43-9
148. Coffman BL, King CD, Rios GR, et al. The glucuronidation of
opioids, other xenobiotics, and androgens by human
UGT2B7Y(268) and UGT2B7H(268). Drug Metab Dispos
1998; 26 (1): 73-7
149. Hecht SS, Carmella SG, Murphy SE. Effects of watercress
consumption on urinary metabolites of nicotine in smokers.
Cancer Epidemiol Biomarkers Prev 1999; 8 (10): 907-13
150. Bogaards JJ, Verhagen H, Willems MI, et al. Consumption of
Brussels sprouts results in elevated alpha-class glutathione S-
transferase levels in human blood plasma. Carcinogenesis
1994; 15 (5): 1073-5
151. Nijhoff WA, Mulder TP, Verhagen H, et al. Effects of con-
sumption of brussels sprouts on plasma and urinary glutathione
S-transferase class-alpha and -pi in humans. Carcinogenesis
1995; 16 (4): 955-7
152. Nijhoff WA, Grubben MJ, Nagengast FM, et al. Effects of
consumption of Brussels sprouts on intestinal and lymphocytic
glutathione S-transferases in humans. Carcinogenesis 1995; 16
(9): 2125-8
153. Lampe JW, Chen C, Li S, et al. Modulation of human gluta-
thione S-transferases by botanically defined vegetable diets.
Cancer Epidemiol Biomarkers Prev 2000; 9 (8): 787-93
154. Benet LZ, Cummins CL. The drug efflux-metabolism alliance:
biochemical aspects. Adv Drug Deliv Rev 2001; 50 (1 Suppl.):
3S-11S
155. Spahn-Langguth H, Langguth P. Grapefruit juice enhances in-
testinal absorption of the P-glycoprotein substrate talinolol.
Eur J Pharm Sci 2001; 12 (4): 361-7
156. Bistrup C, Nielsen FT, Jeppesen UE, et al. Effect of grapefruit
juice on Sandimmun Neoral absorption among stable renal
allograft recipients. Nephrol Dial Transplant 2001; 16 (2):
373-7
157. Becquemont L, Verstuyft C, Kerb R, et al. Effect of grapefruit
juice on digoxin pharmacokinetics in humans. Clin Pharmacol
Ther 2001; 70 (4): 311-6
158. Westphal K, Weinbrenner A, Giessmann T, et al. Oral bioavail-
ability of digoxin is enhanced by talinolol: evidence for in-
volvement of intestinal P-glycoprotein. Clin Pharmacol Ther
2000; 68 (1): 6-12
159. Boyd RA, Stern RH, Stewart BH, et al. Atorvastatin coadmin-
istration may increase digoxin concentrations by inhibition of
intestinal P-glycoprotein-mediated secretion. J Clin Pharmacol
2000; 40 (1): 91-8
160. Dresser GK, Bailey DG, Leake BF, et al. Fruit juices inhibit
organic anion transporting polypeptide-mediated drug uptake
© Adis Data Information BV 2003. All rights reserved.
Harris et al.
to decrease the oral availability of fexofenadine. Clin
Pharmacol Ther 2002; 71 (1): 11-20
161. Johne A, Brockmoller J, Bauer S, et al. Pharmacokinetic
interaction of digoxin with an herbal extract from St John’s
wort (Hypericum perforatum). Clin Pharmacol Ther 1999; 66
(4): 338-45
162. Kovarik JM, Rigaudy L, Guerret M, et al. Longitudinal assess-
ment of a P-glycoprotein-mediated drug interaction of val-
spodar on digoxin. Clin Pharmacol Ther 1999; 66 (4): 391-400
163. Greiner B, Eichelbaum M, Fritz P, et al. The role of intestinal P-
glycoprotein in the interaction of digoxin and rifampin. J Clin
Invest 1999; 104 (2): 147-53
164. Durr D, Stieger B, Kullak-Ublick GA, et al. St John’s Wort
induces intestinal P-glycoprotein/MDR1 and intestinal and
hepatic CYP3A4. Clin Pharmacol Ther 2000; 68 (6): 598-604
165. Krishnaswamy K, Kalamegham R, Naidu NA. Dietary influ-
ences on the kinetics of antipyrine and aminopyrine in human
subjects. Br J Clin Pharmacol 1984; 17 (2): 139-46
166. Kappas A, Anderson KE, Conney AH, et al. Influence of
dietary protein and carbohydrate on antipyrine and theophyl-
line metabolism in man. Clin Pharmacol Ther 1976; 20 (6):
643-53
167. Fagan TC, Walle T, Oexmann MJ, et al. Increased clearance of
propranolol and theophylline by high-protein compared with
high-carbohydrate diet. Clin Pharmacol Ther 1987; 41 (4):
402-6
168. Jorquera F, Almar M, Martinez C, et al. Antipyrine clearance in
surgical patients maintained on hypocaloric peripheral paren-
teral nutrition. JPEN J Parenter Enteral Nutr 1994; 18 (6): 544-
8
169. Burgess P, Hall RI, Bateman DN, et al. The effect of total
parenteral nutrition on hepatic drug oxidation. JPEN J Parenter
Enteral Nutr 1987; 11 (6): 540-3
170. Hoensch HP, Steinhardt HJ, Weiss G, et al. Effects of semisyn-
thetic diets on xenobiotic metabolizing enzyme activity and
morphology of small intestinal mucosa in humans. Gastroen-
terology 1984; 86 (6): 1519-30
171. Maliakal PP, Wanwimolruk S. Effect of herbal teas on hepatic
drug metabolizing enzymes in rats. J Pharm Pharmacol 2001;
53 (10): 1323-9
172. Kusamran WR, Ratanavila A, Tepsuwan A. Effects of neem
flowers, Thai and Chinese bitter gourd fruits and sweet basil
leaves on hepatic monooxygenases and glutathione S-transfer-
ase activities, and in vitro metabolic activation of chemical
carcinogens in rats. Food Chem Toxicol 1998; 36 (6): 475-84
173. Sohn OS, Surace A, Fiala ES, et al. Effects of green and black
tea on hepatic xenobiotic metabolizing systems in the male
F344 rat. Xenobiotica 1994; 24 (2): 119-27
174. Obermeier MT, White RE, Yang CS. Effects of bioflavonoids
on hepatic P450 activities. Xenobiotica 1995; 25 (6): 575-84
175. Umegaki K, Ikegami S. Feeding fish oil to rats accelerates the
metabolism of hexachlorobenzene. J Nutr Sci Vitaminol (To-
kyo) 1998; 44 (2): 301-11
Correspondence and offprints: Dr Robert Z. Harris, Depart-
ment of Pharmacokinetics and Drug Metabolism, Amgen
Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-
1799, USA.
E-mail: harrisr@amgen.com
Clin Pharmacokinet 2003; 42 (13)