Nutrition and pharmacology: general principles and implications for
Daniel J Raiten
Food and nutrition play an intimate and inextricable role in all
aspects of drug metabolism, safety, and effectiveness. Antiretroviral
therapies (ART) have assumed a preeminent position in the preven-
tion, care, and treatment of HIV and its comorbidities. The interac-
tionbetween food,nutrition, andART hasbecome anexpandingarea
of interest both in terms of clinical standards of care and as a target
for research. Since the original review of this topic by the WHO in
2005, much has been learned (8). This article contains a review of
what is known about the general relationships between nutrition and
pharmacology, as well as issues specific to ART, with particular at-
tention to their use in low- and middle-resource settings. The impor-
tance of food and nutrition on the bioavailability of drugs and vice
versa has been an area of historical interest. However, much has been
learned about the importance of nutritional status on drug metabo-
lism, distribution, and effectiveness. The impact of traditional ther-
apies (herbal/botanical) is highlighted as an area of clinical concern
the impact of individual micronutrients on drug pharmacokinetics
and pharmacodynamics. Finally, attention is given to the nutritional
implications of the metabolic consequences of ART, which include
the potential impact of “colliding epidemics” of infection (eg, HIV,
tuberculosis) and noncommunicable diseases. Much has been
learned, but much remains to be accomplished to ensure the effective
integration of nutritional considerations into the effective and safe
use of ART.Am J Clin Nutr 2011;94(suppl):1697S–702S.
Nutrition may be defined as the sum total of the processes
involved in the taking in and use of food substances through
a whole or in any of its parts are accomplished. The processes of
nutrition consist of ingestion, digestion, absorption, metabolism,
functional use/activation of dependent systems, and excretion.
All these processes are similarly integral to how the body takes in
and uses therapeutics/drugs, which include antiretroviral thera-
Not only do drugs and nutrients share these same processes,
their availabilityand function arealso intimately and inextricably
entwined. The body’s ability to process foreign substances
depends on metabolic systems that rely on essential nutrients
(vitamins, minerals, fatty acids, and so forth) obtained through
diet. Yang et al (1) offered a teleologic explanation of the syn-
ergism between diet and the detoxification of foreign substances,
based on the evolutionarychange to a complex diet paradoxically
rich in essential nutrients but that also contained botanical
essential nutrients was linked to the need to develop mechanisms
for detoxification of the accompanying toxins. These mecha-
nisms, in turn, became dependent on many of the same essential
nutrients, which created interdependence between nutrition and
detoxification. In our modern world it is not just exposure to
toxins in theenvironment,butalso theresponse topharmacologic
substances, which, in much the same way as the early botanicals,
are being used on a trial-and-error basis to improve the human
condition. As is the case with exposures to potentially poisonous
herbals/botanicals, exposure to modern medicines can have
toxic, to any foreign substance is contingent on numerous factors
that include stage of development, genetics, general health, and
The general relation between diet, nutrition, and pharmacol-
ogy is conceptualized in Figure 1. It is discussed in the context
of several core concepts, which are outlined in Table 1. Within
the context of pharmacokinetics and pharmacodynamics several
pathways exist by which nutrition might affect drugs and vice
versa (Table 2).
In the context of potential food/nutrient-drug interactions,
most of the available information used clinically is focused on
factors that pertain to drug pharmacokinetics and, in particular,
bioavailability (eg,foods that may affect drug absorption because
of physicochemical solubility relationships). There is, however,
a historical knowledge base with regard to the role of specific
nutrients and pharmacodynamic processes [ie, those Phase I
metabolic systems, mixed-function oxygenase/cytochrome P450
(CYP), responsible for the activation, transport, and excretion of
1From the Endocrinology, Nutrition, and Growth Branch, Center for Re-
search for Mothers and Children, Eunice Kennedy Shriver National Institute
of Child Health and Human Development, National Institutes of Health,
2Presented at the conference “Nutrition in Clinical Management of HIV-
Infected Adolescents (.14 y old) and Adults including Pregnant and Lac-
tating Women: What Do We Know, What Can We Do, and Where Do We Go
from Here?” held in Washington, DC, 26–28 July 2010.
3No funding was provided for this study.
4Address correspondence to DJ Raiten, Eunice Kennedy Shriver National
Institute of Child Health and Human Development, National Institutes of
Health, 6100 Executive Boulevard, Room 4B-11, Bethesda, MD 20892.
First published online November 16, 2011; doi: 10.3945/ajcn.111.019109.
Am J Clin Nutr 2011;94(suppl):1697S–702S. Printed in USA. ? 2011 American Society for Nutrition
drugs (2)]. Examples of these types of interactions are listed in
In addition, a greater appreciation has emerged for the in-
teraction between genes [which includes genetic polymorphisms
in mixed-function oxygenase and related systems (4)] and de-
velopmental changes [eg, in infants, pregnancy, and lactation (5,
6)]. Finally, it is also important to note that the disease process
(eg, inflammation or response to infection) elicits a unique re-
sponse to nutrient homeostasis that affects nutrient absorption,
availability, and response to treatment (7). This is best exem-
plified by the anemia of infection and the impact on iron status,
and the impact of inflammation via the acute-phase response on
the key carriers of iron (eg, ferritin) (8). Thus, a close relation
exists between the body’s response to illness, drugs, nutrients,
and the requisite systems involved in the functional use of the
drugs and nutrients. Many of these concepts are appropriately
applied to environmental toxicants as well and have been dis-
cussed in greater detail elsewhere (2).
NUTRITION AND ART
In 2003, as part of the WHO effort to develop recom-
mendations for the nutritional care of people living with HIVand
AIDS, a review of the extant evidence with regard to the role of
diet and nutrition in the safe and effective use of ART was
requested. The review was released in 2005 (8) and contained 2
overarching principles: 1) antiretroviral drugs are essential to
prolong lives and halt the spread of HIV/AIDS, and 2) food is
essential to life for all people. The challenge then was and now
is how to apply sound principles of clinical care and nutrition
science to the safe and efficacious implementation of ART and
long-term care for people living with HIV and AIDS. Addi-
tionally, the report highlighted the importance of food and ad-
equate dietary intake as essential to achieve optimal nutrition
and health for people before and during treatment of HIV and
related comorbidities. HIV-infected adults and children being
considered for ART should be screened for nutritional problems,
and the extent of such screening will depend on the technical
capacity and level of support at the clinical care setting.
In addition to an outline of the key elements of nutrient-drug
reinforced with new evidence:
d Certain foods affect the bioavailability of antiretroviral medica-
tions; examples included garlic (10, 11) and other traditional
therapies such as African potato (12). Since the original report,
other medicinal plants/herbal remedies have been implicated in
drug interactions (13, 14).
d Use of “traditional medicines” and complementary and alterna-
tive medicines may also affect antiretroviral use (adherence),
efficacy (15), and safety (16).
d A substantial body of evidence exists with regard to the impact of
ART on the metabolism of adults and children; many of these
effects have dietary and nutritional implications (17).
FIGURE 1. Conceptual model of drug-nutrient interactions. ART,
Core concepts of pharmacology1
on microorganisms or parasites within or on the body and the
mechanisms of drug action and the relation between drug concentration
and effect. A prime example is drug-receptor interactions.
The action of drugs in the body over a period of time, including the
processes of absorption, distribution, localization in tissues,
biotransformation, and excretion.
Phases of drug metabolism
Phase IOxidation reduction reactions that result in activation, deactivation, or
preparation for eventual elimination. These reactions occur primarily
in the liver, but also in other tissues (eg, lungs, kidneys, gastrointestinal
tract) and use the synergism between 3 primary components:
d MFO, which include cytochrome P450 enzymes (oxidation)
d NADPH-P450 reductase (reduction)
d Phospholipid (phosphatidylcholine or lecithin). The phospholipid
component provides stability for these membrane-bound enzymes.
The dependence on stable membranes introduces the potential for
damage due to lipid oxidation, which implies a role for antioxidants
in the protection of the integrity of the MFO system.
The attachment of substances, which yields a more polar and
water-soluble substance and thereby facilitates elimination.
Phase II (conjugation reactions)
1MFO, mixed-function oxygenase.
A more direct conceptualization of the model presented in
Figure 1 as it specifically pertains to HIV infection and its
treatment is presented in Figure 2. Aside from the mechanisms
described above, a number of ART-specific interactions may
occur, primarily via the key pathways responsible for drug
metabolism. These include drug-drug interactions, drug-botani-
cal/herbal interactions, and drug-nutrient interactions. Whereas
the principles may differ, the core mechanisms may often be
similar and be mediated via the CYP drug-metabolizing sys-
tems, primarily in the liver and gastrointestinal tract.
ART drug-drug interactions were reviewed recently by
Fletcher (18), who observed that a specificenzyme, CYP3A4, the
most abundant isoform of the cytochrome system in the human
liver, is responsible for the metabolism of ~60% of HIV-related
drugs. Most protease inhibitors and nonnucleoside reverse
transcription inhibitors are CYP3A4 substrates. Therefore, it is
of this enzyme in the use of these drugs. A number of examples
are cited in which one drug affects the use of another via this
mechanism (18). Although the potential for drug interactions is
recognized, what is less well acknowledged is the potential for
interactions between ART and other commonly used substances
through this same mechanism.
The CYP system has been shown to be the target of a number
of other ART interactions with substances commonly used by
HIV-infected patients in domestic/US and international settings.
Mills et al (12) reported on the impact of African herbal med-
icines on antiretroviral metabolism and noted specifically a sig-
nificant inhibition of CYP4A4 by 2 common African herbal
remedies (African potato and Sutherlandia).
Flavonoids are a group of substances that occur naturally in
fruit (including cocoa), vegetables, beverages (tea, wine), and
health conditions. Of particular relevance to this discussion is
evidence that indicates that these compounds significantly affect
the activity (induction or inhibition) of CYP isoforms and other
related drug-metabolizing enzymes (19, 20).
The historical approach to micronutrients in the context of
ART, and more broadly with HIV, is to limit the conversation to
Potential mechanisms to explain drug-nutrient interactions1
Ingestion Both drugs and disease can cause changes in appetite and
nutrient intake; resultant malnutrition can affect drug
Drugsandfoods canhavea mechanicaleffect,via bindingor
adsorption, that can increase or decrease drug and
nutrient absorption. Some drugs can increase or decrease
gastrointestinal motility, which may result in increased or
decreased nutrient absorption. Chemical factors, in
particular the pH of the stomach contents and the
influence of foods therein, can affect the subsequent
absorption of drugs. Nutritional status, infection, and
inflammation can cause homeostatic responses, which
lead to increased or decreased nutrient absorption.
The ability of drugs and nutrients to be transported can
depend on factors such as lipid solubility and competition
for amino acid transport systems.
MFOandconjugasesystems thatconvert drugsand nutrients
into their active and excretory forms are nutrient/cofactor
dependent. Certain drugs can increase the activity of the
MFO systems required to convert nutrient precursors into
their active forms. Nonnutritive components in foods/
supplements can induce MFO activity and thereby affect
The use of both drugs and nutrients depends on body
composition, the availability and functional integrity of
transport proteins, receptor integrity, and intracellular
metabolic machinery, all of which are sensitive to
nutritional status and the impact of disease (inflammation
and infection via the acute-phase response).
Drugs and nutrients can synergistically and competitively
interact to cause increased or decreased excretion.
Systemic factors such as pH and physiologic state (eg,
sweating) can dictate whether a drug or nutrient is
excreted or resorbed.
The effectiveness of some drugs is directly related to their
impact on nutrient metabolism (eg, antimalarial
antifolate drugs, isoniazid, and vitamin B-6).
1MFO, mixed-function oxygenase.
NUTRITION AND PHARMACOLOGY
micronutrient insufficiency (21). However, as evidenced by the
discussions above and below, both low and high micronutrient
With specific regard to nutrients, several have been the focus of
investigation in this context.
Vitamin C has been shown to significantly affect the regulation
of several of the key CYP enzymes, which include isoforms of
CYP, family 3, and subfamily A (CYP3A), some of which were
shown to be decreased by vitamin C deficiency (22). Conversely,
the observation of Slain et al (23) is of particular interest in the
context of ART use. Their study involved the evaluation of the
uninfected subjects who were receiving doses of vitamin C that
ranged from 800 to 1000 mg/d. They reported that “concomitant
administration of high doses of vitamin C can reduce steady-state
indinavirplasma concentrations.”Did theexcessvitaminC result
in increased CYP450 metabolism of indinavir? The clinical
implications of these findings have not been established.
Vitamin D has been highlighted as an important nutrient of
concern for the general public (24). Of relevance here, vitamin D
has also been identified as an nutrient of concern in the context of
HIV, in terms of both nutritional adequacy and specific problems
associated with HIV-related bone problems that are potentially
associated with either nutritional deficiency and/or drug inter-
actions (9, 25). On the other hand, other mechanism(s) by which
vitamin D might have an impact on drug metabolism were de-
scribed by Kutuzova and DeLuca (26), who reported that 1,25-
dihydroxyvitamin D3regulates the genes responsible for the
production of enzymes (including CYP3A4) that are responsible
for detoxification in the intestine. This study has been followed
by numerous others that point to an important and un-
derappreciated role for vitamin D in drug metabolism through
induction of the gene expression of key drug-metabolizing en-
zymes. Consequently, in addition to the concerns about vitamin
D insufficiency associated with poor exposure or nutrient-drug
interactions, there is the potential that vitamin D supplementa-
tion can operate independently through the regulation of the
drug-metabolizing enzymes to affect ART safety and efficacy.
These relationships should be evaluated closely, particularly in
light of the expanding interest in vitamin D supplementation
FIGURE 2. Specific relationships between HIV, treatment, health, and
Examples of the impact of specific nutrients on Phase 1/MFO metabolism1
Nutrient Effect on MFO metabolismPotential mechanism(s)
ProteinDeficiency: Y rate of metabolism
Excess: can [ rate of metabolism
Deficiency (or diet high in saturated fatty acids): Y
Excess (or diet high in polyunsaturated fatty acids): [
activity and induction of MFO enzymes
Y Protein synthesis; Y in synthesis of other elements, such
as hormones, involved in enzyme induction
Y Activity of MFO possibly connected to the requirement
for polyunsaturated fatty acid in the b-position of
phosphatidylcholine (lecithin), which is an essential
component of the MFO system
Secondary effect due to Y protein or possibly inhibition of
P450 via Y in supporting enzyme components
Alterations in activities of P450 and P450 reductase
mediated via either [ or Y in the expression of specific
CYP isozymes in excess or deficiency states
Y Synthesis of heme; possible impairment of protein
[ Activity of specific P450 isozymes and perhaps other
enzymes in deficiency by an unknown mechanism.
Excess may be due to Y substrate binding
Y Reductase activity but [ P450 activity, such that the
metabolism of some drugs will be [, whereas others may
Because activities of P450 and reductase are unaffected, it
may be due to reduction in antioxidative mechanisms (eg,
protection of the lecithin component): lack of effect from
excess may be due to rapid metabolic clearance of
vitamin E isomers via P450 (3)
Differential effects on various components of the MFO
system. [ Lipid peroxidation could lead to damage to the
integrity of the system
Vitamin CDeficiency: Y
Excess: [ P450 activity
Vitamin B-6Deficiency: Y
Thiamine Deficiency: [ activity of cytochrome P450
Excess: Y (both reductase and P450)
RiboflavinDeficiency: Y or [ depending on the severity
Vitamin E Deficiency: Y
Excess: no reported effect
Iron Deficiency: Y and [
Excess: [ in microsomal lipid peroxidation
1Reproduced with permission (2). MFO, mixed-function oxygenase.
across all segments of the population, including HIV-infected
Vitamin A continues to hold a position of great interest in the
global health dialogue and vitamin A insufficiency continues to
be a major concern (28, 29). Again, most of the focus of the
been on insufficiency. Several lines of evidence have indicated
that vitamin A supplementation may be an issue of concern,
particularly for HIV infection (30, 31).
With specific regard to drug metabolism, evidence similar to
that for vitamin D and vitamin C exists for an important role for
vitamin A. Vitamin A has 3 active forms (retinal, retinol, and
retinoic acid) and a storage form (retinyl ester):
Retinyl ester 4 Retinol 4 Retinal / Retinoic acid
Investigators have reported that 3 primary forms of vitamin A
(9-cis-retinal, 9-cis-retinoic acid, and all-trans-retinoic acid)
induce CYP3A expression at messenger RNA, as well as en-
zyme activity levels in both liver and intestinal cells (32). The
study by Chen et al (33) showed that, in their model, retinoids
were able to alter drug metabolism through CYP3A induction.
These reports reinforce the notion that the use of vitamin A
supplements may have implications mediated through this role
in drug metabolism, which will require further research and
It is clear that in light of what we know about the processes of
nutrition and pharmacology, the view of nutrition and specific
nutrients must be expanded beyond the desire to prevent and treat
undernutrition. Moreover, the use of dietary supplements,
whether in the form of traditional therapies (herbal/botanical) or
as nutrient supplements intended to correct presumed in-
sufficiency, must beviewed in a larger context. This context must
include the health of the individual [the presence or absence of
active disease (either communicable and/or chronic), de-
velopmental stage, nutritional status (replete or deplete)] and the
potential impact of these bioactive substances on all aspects of
This article has provided an overview of the potential role of
nutrition and specific nutrients and other dietary substances in the
safe and effective use of ART. A description of these phenomena
is just the first step. In terms of care and treatment, what do we
need to do to improve our clinical approach? What does it all
mean and what can we do?
To start, we have to look more carefully at potential drug-
nutrient interactions in the clinical setting and to ask the correct
questions, particularly in settings in which poor nutrition might
be anticipated. To support our ability to do that, we need to
delineate more clearly the role of nutrients in pharmacology
beyond just bioavailability. We also need to look more critically
at the nutritional context in which people live and to ask some
basic questions at the initial visit, such as “Are you hungry?,”
‘”Whatareyou eating?,”and“Areyou usingdietary supplements
and/or traditional therapies?” From a public health perspective
a need exists to examine more closely the “one-size-fits-all"
public health approach to nutrition, particularly as it relates to
micronutrients and especially in the context of infections such as
HIVand their treatment (34). We cannot limit our focus to only
amelioration of undernutrition. The provision of additional
micronutrients in some scenarios may, in fact, exacerbate rather
than ameliorate problems. Our ability to determine when that
might be the case will depend on our evolving knowledge about
these complex relationships as well as our access to the tools
needed to evaluate them (eg, biomarkers) for accurate and re-
liable assessment of nutritional status.
Much work has been done to address the important synergies
between food, nutrition, and the safe and effective imple-
mentation of ART use to prevent and treat HIV. However,
continued effort and vigilance is needed to ensure that these
issues are fully integrated into prevention, care, and treatment
programs. Only through such efforts can we achieve the goals of
all the global efforts to address this compelling and ongoing
global health challenge.
The author had no conflict of interest.
1. Yang CS, Brady JF, Hong JY. Dietary effects on cytochromes P450,
xenobiotic metabolism, and toxicity. FASEB J 1992;6:737–44.
2. Raiten DJ. Nutrition, pharmacology, and toxicology: a dialectic. In:
Massaro E, ed. Handbook of human toxicology. Boca Raton, FL: CRC
3. Traber MG. Regulation of xenobiotic metabolism, the only signaling
function of alpha-tocopherol? Mol Nutr Food Res 2010;54:661–8.
4. Johansson I, Ingelman-Sundberg M. Genetic polymorphism and toxicol-
ogy—with emphasis on cytochrome P450. Toxicol Sci 2011;120:1–13.
5. Ward RM, Lane RH, Albertine KH. Basic and translational research in
neonatal pharmacology. J Perinatol 2006;26(Suppl 2):S8–12.
6. McCarter-Spaulding DE. Medications in pregnancy and lactation.
MCN Am J Matern Child Nurs 2005;30:10–7, quiz 18–9.
7. Prentice AM, Ghattas H, Cox SE. Host-pathogen interactions: can
micronutrients tip the balance? J Nutr 2007;137:1334–7.
8. Northrop-Clewes CA. Interpreting indicators of iron status during an
acute phase response–lessons from malaria and human immunodefi-
ciency virus. Ann Clin Biochem 2008;45:18–32.
9. Raiten DJ, Grinspoon S, Arpadi S. Nutritional considerations in the use
of ART in resource-limited settings. Geneva, Switzerland: World
Health Organization, 2005.
10. Piscitelli SC, Burstein AH, Welden N, Gallicano KD, Falloon J. The
effect of garlic supplements on the pharmacokinetics of saquinavir.
Clin Infect Dis 2002;34:234–8.
11. Berginc K, Milisav I, Kristl A. Garlic flavonoids and organosulfur
compounds: impact on the hepatic pharmacokinetics of saquinavir and
darunavir. Drug Metab Pharmacokinet 2010;25:521–30.
12. Mills E, Cooper C, Seely D, Kanfer I. African herbal medicines in the
treatment of HIV: Hypoxis and Sutherlandia. An overview of evidence
and pharmacology. Nutr J 2005;4:19–25.
13. Brown L, Heyneke O, Brown D, van Wyk JP, Hamman JH. Impact of
traditional medicinal plant extracts on antiretroviral drug absorption. J
14. Wiegman DJ, Brinkman K, Franssen EJ. Interaction of Ginkgo biloba
with efavirenz. AIDS 2009;23:1184–5.
15. Peltzer K, Friend-du Preez N, Ramlagan S, Fomundam H, Anderson J.
Traditional complementary and alternative medicine and antiretroviral
treatment adherence among HIV patients in Kwazulu-Natal, South
Africa. Afr J Tradit Complement Altern Med 2009;7:125–37.
16. Ladenheim D, Horn O, Werneke U, Phillpot M, Murungi A, Theobald
N, Orkin C. Potential health risks of complementary alternative med-
icines in HIV patients. HIV Med 2008;9:653–9.
17. Fitch K, Grinspoon S. Nutritional and metabolic correlates of cardio-
vascular and bone disease in HIV-infected patients. Am J Clin Nutr
18. Fletcher CV. Antiretroviral drug-drug interaction considerations for
HIV-infected children. Pediatr Infect Dis J 2009;28:429–30.
NUTRITION AND PHARMACOLOGY